International Journal of Human Anatomy

International Journal of Human Anatomy

International Journal of Human Anatomy

Current Issue Volume No: 1 Issue No: 3

Review Article Open Access Available online freely Peer Reviewed Citation

Oligodendrocytes Development and Wnt Signaling Pathway

Shahid Hussain Soomro 1,   Jifu Jie 2,   Hui Fu 3  

1Wuhan University, School of Basic Medical Sciences, Department of Anatomy.

2Department of Anatomy, Health School of Bayinguoleng Mongolian Autonomous Prefecture, Korla, Xinjiang, China.

3Shenzhen Institute of Wuhan University, Shenzhen, china.

Abstract

Oligodendrocytes are specialized glial cell in central nervous system (CNS) responsible for the formation of myelin sheath around the axon. Oligodendrocyte proliferation and differentiation is regulated by Wnt signaling pathway, at various stages. However, different study groups have described controversial conclusions about the effect of Wnt on oligodendrocytes precursor cells (OPCs) development. Initially it has been proposed that Wnt pathway negatively regulates the OPCs proliferation and differentiation but recently some studies have described that Wnt promotes the differentiation of OPCs. After carefully reviewing the literature, we believe that Wnt play multiple roles in OPCs differentiation and its function is time (stage) and dose sensitive. Low to moderate activation of Wnt promotes OPC development, while too much or too low is inhibitory. Current evidences also suggested that in early developmental stages, Wnt inhibits the OPCs formation from neural progenitors and differentiation into immature oligodendrocytes. But in late stages Wnt plays promoting role in differentiation and maturation of oligodendrocytes. This review summarized the updated information regarding the critical role of Wnt signaling cascade in proliferation and differentiation of OPCs.

Author Contributions
Received 29 Sep 2018; Accepted 22 Oct 2018; Published 29 Oct 2018;

Academic Editor: Abdelmonem Awad Mustafa Hegazy, Professor and Former Chairman of Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Egypt.

Checked for plagiarism: Yes

Review by: Single-blind

Copyright ©  2018 Shahid Hussain Soomro, et al. 

License
Creative Commons License     This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Competing interests

The authors have declared that no competing interests exist.

Citation:

Shahid Hussain Soomro, Jifu Jie, Hui Fu (2018) Oligodendrocytes Development and Wnt Signaling Pathway. International Journal of Human Anatomy - 1(3):17-35. https://doi.org/10.14302/issn.2577-2279.ijha-18-2407

Download as RIS, BibTeX, Text (Include abstract )

DOI 10.14302/issn.2577-2279.ijha-18-2407

Introduction

Oligodendrocytes (OLs) are specialized glial cell in central nervous system (CNS) responsible for the formation of myelin sheath around the axon which not only help in rapid conduction of electrical impulses but also provides metabolic and trophic support to underlying axon. Loss or damage to myelin sheath may result in various devastating neurological disorders including multiple sclerosis (MS), cerebral palsy and others 1, 2, 3, 4. Fortunately, the CNS has an excellent capacity to regenerate myelin sheath, in healthy individuals as well as in the early course of diseases 5. However, during a prolonged disease course with recurrent attacks of demyelination, remyelination eventually fails leading to various demyelinating diseases 6, 7, 8. It is therefore critical to understand the cellular and molecular mechanisms that regulate myelination in order to develop novel therapies to target remyelination 2, 9, 10, 11, 12, 13. In mammals, myelination process occurs during postnatal development 14, 15. OLs development, from an oligodendrocyte precursor cell (OPC) to a mature myelinating OL, is controlled by a number of both inhibitory and inductive factors. Either failure of the mechanisms that promote myelination or the presences of strong inhibitory molecular signals suppress OPC differentiation and myelination. Important regulators of OL differentiation are electrical activity 16, 17, molecular signals derived from axons 18 and various extrinsic and intrinsic pathways. Among them Wnt signaling pathway is one of the critical pathways involved in the development of oligodendrocyte precursor cell. Wnt is one of the complex pathways with controversial role in the development of OLs. It affects many developmental stages of the OL lineage, with different effects. In this review we will discuss in detail about oligodendrocytes, Wnt (canonical) signaling pathway and its effect on OPCs development. This review will also highlight various targets of Wnt signaling pathway, which can be used or further investigated for the treatment of demyelinating diseases.

Functions of Oligodendrocytes

Oligodendrocytes are non-dividing cells, responsible for myelination in CNS. Mature oligodendrocytes form myelin sheath which provides critical insulation to facilitate axonal conduction by increasing the resistance and lowering the capacitance of the axonal membrane, resulting in faster conduction speed in myelinated axons than in unmyelinated axons of the same diameter 19. The number of oligodendrocytes in any region of the CNS broadly depends upon, the number of OPCs migrating toward that region, the proliferative potential of the resident OPCs prior to differentiation and number of cells lost. All these factors ultimately affect the smooth and effective myelination process20.

Oligodendrocytes Development

Oligodendrocytes are mature glial cells present in CNS derived from their precursor cells, commonly called as Oligodendrocyte precursor cells (OPCs). During the formation of CNS, OPCs are derived from neural stem cells. Around embryonic day (E12.5) OPCs are derived from pMN domain located at ventral midline of caudal portion of neural tube 21. About 2 days later around E15, OPCs are also arises from dorsal spinal card. This is known as second wave of OPCs generation 22, 23 Third wave also developed after birth from cerebral cortex which give rise that most of the population of OPCs present in adult brain 24, 25.

The development of Oligodendrocytes lineage cells from their precursors to mature form is a complex process during which the cells exhibit morphological and biochemical changes. These diversities help to identify OLs lineage cells in various stages beneficial to adjust different targets for the treatment of demyelinating diseases. The development and maturation of oligodendrocytes require a series of highly-coordinated events that organise the proliferation and differentiation of the OPCs as well as the spatio-temporal regulation of myelination. After differentiation from neural stem cells, first recognized stage of oligodendrocytes lineage cells is OPCs. In this stage cells exhibit various markers including, Nestin, PSA-NCAM, PDGFRα and NG2. Among them, platelet-derived growth factor receptor α (PDGFRα) transcript is unique for oligodendrocytes at very early stages of development 26, 27. First signs of OPC maturation into oligodendrocytes and myelination can be observed around E17 and these processes continue after birth 28, 29. As OPCs start process of maturation, they lose their proliferative and migratory capacity and their shape change to complex one 30. Oligodendrocytes precursor cells when start differentiation, they express monoclonal antibody O4, and are termed pro-oligodendroblast 31. With further development OPCs are differentiated in immature oligodendrocytes. In this stage oligodendrocytes express galactocerebroside (GalC) and 2′,3′-cyclic nucleotide 3′-phosphodihydrolase (CNPase). From this pre-myelinating immature stage oligodendrocytes are differentiated in to mature myelin forming oligodendrocytes where they express Myelin Basic Protein (MBP), ProteoLipid Protein (PLP), Myelin-Associated Glycoprotein (MAG), and Myelin/Oligodendrocyte Glycoprotein, as well as other minor myelin proteins 32.

In the developmental myelination, OLs lineage cells are tightly regulated by various factors. These factors include growth factors, protein kinases, extracellular matrix, intracellular signaling cascade and soluble molecules. All these factors influence epigenetic modifications, transcriptional & translational regulation, and the actin cytoskeleton in oligodendrocytes 33, 34, 35, 36, 37. Oligodendrocytes differentiation result from transcriptional changes in gene expression and is favoured by sonic hedgehog (Shh) (38, 39), thyroid hormone 38, 39, 40, 41, IGF142, 43 and retinoic acid 44 and antagonized by mitogenic stimuli such as PDGF and FGF 40, 45, 46, 47, Wnt 48, 49, Notch 50, 51 and BMP4 52, 53, 54, 55. The progression from OPCs to mature oligodendrocytes occurs in stages and is characterized by complex cytoskeletal organization 28 and progressive chromatin compaction 56, 57. Various researchers have previously reported that changes of acetylation levels in nucleosomal histones, the basic unit of chromatin, are critical for oligodendrocyte differentiation in the developing brain and in repair after demyelination in adult mice 58, 59, 60, 61, 62

Wnt Signaling Pathway

Wingless and integration site (Wnt) signaling cascade are a group of  proteins, responsible for signals transmission from cell surface receptors to the nucleus where gene transcription carried out 63. Wnt signaling is one of the fundamental mechanisms that direct cell proliferation, cell polarity and cell fate determination during embryonic development and tissue homeostasis 64. Therefore mutations in the Wnt signaling pathway are often related to congenital diseases, carcinomas and other diseases 65.

Types

Since last two decades, Wnt/β-catenin signaling has emerged an important pathway involved in many cellular processes. Wnt signaling pathway is of two types, canonical and non-canonical. Canonical Wnt signaling pathway plays essential roles in cell proliferation, migration, invasion and metastasis66 while non-canonical Wnt pathway activates T cell related transcription to modulate cytoskeleton rearrangement, cell adhesion, migration and tissue separation67. Non-canonical Pathway again has been divided into two types, the planar cell polarity pathway and Wnt/Ca2+ pathway. In the planar cell polarity pathway, frizzled activates JNK and directs asymmetric cytoskeletal organization and coordinated polarization of cells within the plane of epithelial sheets. The Wnt/Ca2+ pathway leads to release of intracellular Ca2+, possibly via G-proteins. Elevated Ca2+ can activate the phosphatase calcineurin, which leads to dephosphorylation of the transcription factor NF-AT in the nucleus, where it causes the transcription of many genes. Role of canonical pathway in myelination and remyelination has been well investigated. Therefore in this review we mainly focused on canonical Wnt signaling pathway.

Canonical Wnt Signaling Pathway

In mammals, canonical Wnt signaling pathway consist of four components, Wnt ligands/proteins family (extracellular), frizzled receptors (located at surface membrane) along with low density lipoprotein receptor related protein-5 & 6 (LRP-5/6), β-catenin (cytoplasmic) and LEF/TCF transcription factors (intranuclear) 68. Wnt pathway is activated by binding of Wnt ligand to surface receptors, seven-transmembrane domain Frizzled receptors (Fzd) and single-transmembrane domain co-receptor Lrp5/669. This binding causes the degradation of “β-catenin destruction complex”, which consists of adenomatous polyposis coli (APC), Axin, glycogen synthase kinase 3 β (Gsk3- β), and casein kinase 1 (CK1). β-catenin destruction complex degradation results in accumulation of β-catenin in the cytoplasm and starts entering into the nucleus where it binds to TCF4 and activates downstream gene e.g CyclinD, c-myc, CD4470. Finally this results in cell proliferation, differentiation, metastasis, chemo-resistance and other biological effects. When Wnt is not activated, cytoplasmic β-catenin is degraded by β-catenin destruction complex. This degradation results from phosphorylation of β-catenin at amino terminal region by CK1 and GSK3-β. After phosphorylation β-catenin is recognized by β-Trcp, an E3 ubiquitin ligase subunit, followed by β-catenin ubiquitination and proteasomal degradation 71. In the absence of β-catenin, Wnt target genes are repressed by the DNA-bound T cell factor/lymphoid enhancer factor (TCF/ LEF) family of proteins.

Wnt Components

Wnt Ligands

Wnt ligands are conserved in all metazoan animals. Presence of 19 Wnts in mammals, indicate complexity and specificity of Wnt signaling pathway. Wnts are cysteine rich proteins of approximately 350-400 amino acids that contain an N-terminal signal peptide for secretion. Murine Wnt3a represents the first purified and biochemically characterized Wnt protein 72. Wnt ligands represent secreted molecules, having extensive capacity for inhibiting differentiation of OPCs 20. Fancy et al, identify changes in the expression of multiple Wnt ligands following the induction of demyelination. This further strength their role in remyelination process 48. Identifying the cells responsible for secreting these ligands could broaden our understanding regarding demyelinated environment, which help in potential therapeutics development.

Wnt Receptors: Frizzled and LRP5/6

Wnt/β-catenin signaling pathway, for its function, required two distinct receptor families including, the Frizzled (Fz or Fzd) seven-pass transmembrane receptors (64) and the LDL receptor-related proteins 5 and 6 (LRP5 and LRP6) 71. The mammalian genome contains 10 Fz genes, most of which have variable capacities to activate Wnt/β-catenin signaling when co-overexpressed with Wnt and LRP5/6 73. Among LRPs, LRP6 plays a more dominant role and is essential for embryogenesis whereas LRP5 is dispensable for embryogenesis but critical for adult bone homeostasis. Collectively LRP5 and LRP6 play critical role for the mouse gastrulation 71. Activation of canonical and/or non-canonical pathway also depends upon the binding of Wnt ligand to receptor complement 63. Fz function is involved in β-catenin and non-canonical pathways. The Fz-LRP5/6 co-receptor model describes that a Wnt-Fz binding capable of recruiting LRP5/6, thus activates the β-catenin pathway 71. However some studies suggest that LRP6 antagonizes non-canonical Wnt signaling in vivo, possibly via competing for Wnt ligands 74 or an unknown mechanism 75. Some other Wnt receptors also have been identified such as Ryk and ROR2, which usually have no/little function, but in some cases may antagonize, Wnt/β-catenin signaling 63.

Wnt Antagonists & Agonists

Wnt/β-catenin signaling are antagonized or modulated by various secreted proteins. Among them sFRPs (secreted Frizzled related proteins), and WIF (Wnt inhibitory protein) bind to Wnt, while sFRPs also binds to Fz, and thereby act as Wnt antagonists for both β-catenin and non-canonical signalling76.

Apart from these, Dickkopf (Dkk) and Wise/SOST families also function as Wnt inhibitors. Dkk family proteins function as LRP5/6 ligands/antagonists, thus are considered specific inhibitors for canonical Wnt signaling pathway. Dkk1 inhibits Wnt signaling through LRP6 internalization/ degradation via transmembrane Kremen (Krm) proteins 77. Some opponent studies argue that Dkk1 disturbed the Wnt-induced Fz-LRP6 complex formation and by this mechanism it act as inhibitor 78, while Krm plays a minor modulatory role in specific tissues 79. Like Dkk1, SOST disrupt Wnt-induced Fz-LRP6 complex formation in vitro 80, and by this way it inhibits Wnt/ β-catenin signaling. Shisa family proteins are another wnt Inhibitors, which prevent Fz from reaching to cell surface, thus inhibit Wnt/β-catenin signaling autonomously 81. Some other Wnt/ β-catenin signaling antagonists with multivalent activities have also been identified. IGFBP-4 (Insulin-like growth-factor binding protein-4) binds to both Fz and LRP6 and antagonizes Wnt/β-catenin signaling, further it also modulates IGF signaling 82.

Among the agonists, Norrin and R-spondin (Rspo) proteins are two distinct families, for Wnt/β-catenin signaling, have been identified. Norrin acts by binding to Fz4 and LRP5/6 during retinal vascularization 83. Rspo proteins show synergy with Wnt, Fz and LRP6 84, 85, 86, 87, and genetic interaction with LRP6 during embryogenesis 88. Norrin and Rspo exhibit controversial mechanism of actions. Rspo binds to Fz and LRP6 both or individually, has been reported in some studies 86, 87 while another study reported that Rspo is a ligand for Krm and antagonized Dkk/Krm-mediated LRP6 internalization 73. Review of literature revealed that Rspo activates Wnt/β-catenin by antagonizing LRP6 internalization. This looks less likely mechanism as Krm1/2 (causes LRP6 internalization with Dkk1) double knockout mice were viable and do not show mutant phenotype, further Rspo activated Wnt/β-catenin signaling in cells lacking both Krm genes 79, 88. Rspo genes are often co-expressed with and depend on Wnt for expression 84, and may represent a means of positive feedback that reinforces Wnt signaling.

β-catenin

β-catenin is essential component of Wnt signaling pathway, essential intracellular protein, encoded by CTNNB1 gene in human beings. Mutations (deletion or over expression) of β-catenin are associated with many cancers 89, cardiac and demyelination diseases.

In the case of Wnt “Off”, β-catenin is phosphorylated and degraded. The scaffolding protein Axin uses separate domains to interact with GSK3, CK1α, and β-catenin and coordinates sequential phosphorylation of β-catenin at serine 45 by CK1α and then at threonine 41, serine 37 and serine 33 by GSK3 90. β-catenin phosphorylation at serine 33 and 37 creates a binding site for the E3 ubiquitin ligase β-Trcp, leading to β-catenin ubiquitination and degradation. Mutations of β catenin at and surrounding these serine and threonine residues are frequently found in cancers. But when Wnt is “On”, β-catenin not phosphorylated, accumulated in cytoplasm, then enters into the nucleus, binds to TCF7l2 and causes genes transcription.

TCF/LEF

The TCF/LEF family transcription factors mostly bind to β-catenin and cause genes regulation 91, 92. TCF represses gene expression by interacting with the repressor Groucho (TLE1 in human), which promotes histone deacetylation and chromatin compaction. β-catenin stabilization and nuclear accumulation leads TCF/β-catenin complex formation, which displace Groucho 93 and recruits other co-activators for gene activation. In mammalian, four TCF/LEF family genes are present including, LEF1, TCF1, TCF3 and TCF4. Alternative splicing and promoter usage produce a large number of TCF variants with distinct properties 91, 92. TCF proteins are HMG (high mobility group) DNA-binding factors, bind to a DNA consensus sequence known as Wnt responsive element (WRE). A genome-wide analysis in colon carcinoma suggested that TCF4/β-catenin target genes have multiple WREs, most of which are located at large distances from transcription start sites 94. Some TCF1 and TCF4 splicing variants have another DNA-binding domain called C-clamp, which recognizes an additional GC element downstream of the typical WRE, allowing different sets of target genes regulation 95.

TCF1 and TCF4 act as both repressors and activators, LEF1 usually acts as activator whereas TCF3 mostly exhibits repressor function but sometimes behaves as activator as well 91, 92. TCF/β-catenin induced transcription is mostly regulated by three strategies including, (i) Alternative promoter usage in TCF-1 and LEF-1 genes produces dnTCF-1/dnLEF-1, which lack the amino-terminal β-catenin-binding domain and thus act as the endogenous dominant negative TCF/LEF 91, 92. (ii) dnTCF-1, antagonizes TCF-4 in stem cell renewal, thus causes tumor suppression 49. Chibby and ICAT (Nuclear antagonists) bind to β-catenin and disrupt β-catenin/ TCF and β-catenin/co-activator interactions, thus promote β-catenin nuclear export 96, 97. Apart from these antagonists, KLF4 also acts as inhibitor and prevents β-catenin transcriptional activation, critical for tumor suppression 98.

TCF/LEF can undergo post-translational modifications including phosphorylation, acetylation, sumoylation, and ubiquitination/degradation 91, 92. These modifications result in activation or suppression of downstream genes. TCF-3 phosphorylation by CK1 and LEF-1 phosphorylation by CK2 enhances their binding to β-catenin and diminishes LEF-1 binding to Groucho/TLE, whereas LEF-1 and TCF-4 phosphorylation by NLK (Nemo-like kinase) leads to deceased LEF/TCF/β-catenin complex binding to DNA and their degradation. LEF-1 and TCF-4 sumoylation represses LEF-1 activity by targeting it to nuclear bodies but enhances TCF-4/β-catenin transcription. These modifications of TCF/LEF proteins may result in their paradoxal role.

Self-Regulation of Wnt Signaling Pathway

Wnt/β-catenin signaling regulates proliferation, fate specification and differentiation in different developmental stages and various adult tissues homeostasis. Therefore Wnt target genes show diversity 99 and cell- and context-specificity 64. Wnt signaling components including Fz, LRP6, Axin2, TCF/LEF, Dkk1, and Rspo, are often regulated positively or negatively by TCF/β-catenin 64, 84, 100, 101. Wnt induction of Axin2, Dkk1, Naked and suppression of Fz and LRP6 constitute negative feedback loops that suppressed Wnt signaling 64. Contrary, Wnt induction of Rspo and TCF/LEF genes constitute positive feedback and reinforce Wnt signaling 102, 103. These various Wnt pathway self-regulatory loops are mostly utilized in a cell-specific manner, providing further complexity in the control of amplitude and duration of Wnt responses.

Wnt Signaling and Diseases

Wnt/β-catenin signaling pathway plays a critical role in development and homeostasis. Therefore, there is no surprise that its mutations would be associated with many hereditary disorders, demyelinating diseases, carcinomas and other diseases (Table 1). These mutations involve various Wnt ligands, agonists and antagonists, and affect on Wnt regulation of human development leading to various disease processes. For example, RSPO1 mutations result in XX sex reversal 104, a condition having similar features to patients with WNT4 mutations 105. FZ4 or LRP5 mutations are associated with familial exudative vitreo-retinopathy (FEVR) 106, manifested by defective retinal vascularization 83. LRP5 loss-of-function mutations has been identified in patients with osteoporosis pseudo-glioma syndrome (OPPG), a recessive disorder characterized by low bone mass and abnormal eye vasculature 107, while LRP5 missense (‘gain-of-function’) mutations has been observed in patients with autosomal dominant high bone mass (HBM) diseases 108, 109.

Table 1. Wnt components mutations related diseases
Wnt3(158) Ligands for Wnt/βcatenin signaling LOF Tetra-amelia
Wnt4(105) Ligands for Wnt/βcatenin signaling LOF Mullerian-duct regression and viriliation
Wnt5b(159) Ligands for Wnt/βcatenin signaling Type II diabetes (?)
Wnt7a(160) Ligands for Wnt/βcatenin signaling LOF Fuhrmann syndrome
Wnt10a(161) Ligands for Wnt/βcatenin signaling LOF Odonto-onchyo-dermal hypoplasia
Wnt10b(162) Ligands for Wnt/βcatenin signaling LOF Obesity
RSPO1(104) Wnt agonist LOF XX sex reversal with palmoplantar hyperkaratosi
RSPO4(163) Wnt agonist LOF Autosomal recessive anonychia and hyponychia congenita
SOST(164) LRP5/6 antagonist predominantly expressed in osteocytes LOF High bone mass, Sclerosteosis, Van Buchem disease
Norrin (83, 164) Specific ligand for FZD4 and LRP5 during eye developmen LOF Familial Exudative vitreoretinopathy
LRP5(108, 165) Wnt co-receptors GOF Hyperparathyroid tumors GOF High bone mass LOF Osteoporosis-pseudoglioma LOF FEVR eye vascular defect
LRP6(166) Wnt co-receptors LOF Early coronary disease and osteoporosis
FZD4(167) Wnt receptor LOF Familial Exudative vitreoretinopathy
Axin1(168, 169) Facilitates β-catenin degradation, Tumor suppressor LOF Caudal duplication, Cancer
Axin2(170, 171) Facilitates β-catenin degradation, Tumor suppressor LOF Tooth agenesis, Cancer
APC(172, 173) Facilitates β-catenin degradation, Tumor suppressor LOF Familial adenomatous polyposis, Cancer
WTX(174, 175) Facilitates β-catenin degradation, Tumor suppressor LOF Wilms tumor
β-catenin(CTNNB1)(176, 177) Primary Wnt effector, Oncogene GOF cancer
TCF4 (TCF7L2)(110, 178) + β-catenin transcriptional partner Type II diabetes (?)

• LOF: loss-of-function; GOF: gain-of-function

TCF7L2 has strong relationship with diabetes mellitus type II 110. Although the diabetes-associated TCF7L2 gene polymorphism does not alter protein coding, but its association with the disease has been confirmed in numerous populations 111. Some studies have suggested that the predisposing TCF7L2 variant causes a decreased insulin secretion from pancreatic β-cells, but other pathogenic mechanisms involving additional tissues/organs or endocrine functions remain to be elusive.

Demyelinating diseases also caused by dysregulation of Wnt signaling pathway. Wnt controls multiple aspects of OL development including the specification of OPCs, OPCs differentiation, myelination, and remyelination. Here Wnt shows paradoxal role. It’s promoting and inhibitory effects are under great debate along with the timing and intensity of Wnt activation. Wnt signaling dysregulation with cancer has been well documented, particularly with colorectal cancer 112. Constitutively activated β-catenin signaling, prevent its degradation, leads to excessive stem cell renewal/proliferation that predisposes cells to tumorigenesis 113.

Nkx2-2 and Oligodendrogenesis

Nkx2.2 regulates the expression of myelin structure genes and oligodendrocyte differentiation. It is plausible that the Nkx2.2 homeodomain transcription factor may directly bind to the promoters of MBP and PLP genes and subsequently regulate their expression 114. Common binding sites for Nkx2.2 are found in PLP and MBP promoters, thus overexpression of Nkx2.2 transcription factor can induce gene expression from the PLP promoter in transient transfection assays 114. In Nkx2.2 knockout mice, the number of myelin basic protein (MBP)-positive and proteolipid protein (PLP)-positive oligodendrocytes is drastically reduced and delayed in both the spinal cord and the brain. PLP and MBP expression is not inhibited completely, which indicates that Nkx2.2 may have a partially redundant function with other transcription factors such as Olig1/Olig2 or Sox10 which are co-expressed in oligodendrocyte progenitors. It is possible that Nkx2.2 may enhance or modulate the activities of these transcription factors. Wnt signaling pathway also plays its role in expression of Nkx2-2. Wnt pathway inhibitors regulate the threshold response of a ventral Shh target gene, Nkx2.2, to establish its restricted expression in the ventral spinal cord. Identification and characterization of an Nkx2.2 enhancer reveals that expression is directly regulated positively by Shh signaling and negatively by TCF7l2 repressor activity.

BMP4 and Oligodendrocytes Development

OPCs Differentiation results from the integration of extracellular signals and the chromatin state of a cell. OPCs are characterized by euchromatin and amenable to “accept” environmental signals (i.e Wnt, Shh, Bmp4, Notch) to modulate gene expression and differentiation. Impaired OPCs generation after Shh loss-of function 115 and ectopic oligodendrogenesis after Shh gain-of function has been reported 38, 116. BMP4 increases the number of astrocytes at the expenses of oligodendrocytes 52, inhibits differentiation at later stage 53 and decreases myelin genes expression 54, 117, 118, 119. BMP4 signals activate Smad1/5/8 proteins (R-Smads), associate with the common mediator-Smad 4 (co-Smad) 120, 121 and activate gene expression by interacting with transcription co-activators 122, 123. In OPCs competitive mechanism between Shh and BMP4 has been identified 118. It involved the functional sequestration of Shh target molecules (i.e. Olig2) by the inhibitors of Id2 and Id4 (differentiation protein), which are induced by BMP4 124, 125, 126, 127. In mouse cerebellar cultures, in contrast, BMPs interfere with the Shh-induced proliferation by decreasing the levels of Gli1 and Smo 128, while in the chick spinal cord, BMP has been shown to repress Shh target genes Olig2 and Nkx2.2 129. In the adult brain the inhibitory effect of BMP4 on oligodendrogliogenesis has been attributed to the effect of Smad4 on the expression of Olig2. In a series of elegant studies on mice lacking Smad4 in neural stem cells, higher numbers of Olig2+ cells and oligodendrocytes were detected, a finding that was replicated by infusion of noggin (BMP inhibitor) 130. High levels of BMP4 have been reported in human brains from Multiple Sclerosis patients 131, in animal models of spinal cord injury, 132, in mice with induced experimental allergic encephalomyelitis 133 and in the cuprizone-induced demyelination model and they correlated with a dose-dependent increase of the astrocyte number at the expenses of oligodendrocytes 134. The inhibition of BMP4 signaling by infusion of noggin reversed the effect and reduced the astrocyte numbers 134 while promoting oligodendrocyte regeneration and remyelination 135.

Wnt Signaling Pathway and OPCs Development

The Wnt pathway is a key signaling mechanism that controls multiple aspects of OL development including the specification of OPCs, OPCs differentiation, myelination, and remyelination. Wnt signaling via the canonical pathway is transiently activated in OPCs at the time of initial differentiation and then down-regulated when oligodendrocytes get mature 48, 136. Initial specification of the oligodendrocyte lineage requires coordination of various upstream and downstream transcription factors 23, 137 including Tcf7l2, for the generation of mature, post-mitotic oligodendrocytes 58. In contrast to other signaling pathways, Wnt shows paradoxal role in OPCs proliferation and differentiation. Effect of Wnt depends upon stage of maturation at the time of activation and intensity of activation.

Inhibitory Effect of Wnt on OPC Development

The Wnt signaling pathway was initially described as an OL development inhibitor in embryonic spinal cord cultures 138. Later on multiple in vivo studies confirmed that Wnt plays an inhibitory role in OPC differentiation during early postnatal development 48, 58, 139. Azim et al in their study observed the negative impact of Wnt3a ligand on the OPCs differentiation. By the addition of Wnt3a agonist, Sox10+ OPCs and OLs were increased while significant decrease was observed in PLP+ OLs 140. Lee et al reported that Wnt signaling, when antagonised by Apcdd1, which binds to LRP6 receptor and blocked its function, promotes OPCs differentiation 141. Daam2 is required for canonical Wnt signaling during patterning in the dorsal spinal cord, functioning through the clustering and formation of Wnt receptor signalosomes 142. Suppression of Wnt signalling pathway in Daam 2 knockout mice resulted in increased number of MBP+ and PLP+ OLs, further supporting that Wnt plays an inhibitory role in differentiation process 143. OPC differentiation was also delayed following Wnt pathway activation by expressing a dominant-active β-catenin specifically in cells of the OL lineage 48, 139. Loss of APC or Axin2, stabilizes the β-catenin and exerts an inhibitory effect on myelination 144, 145, 146, 147. Similarly pharmacological agent (XAV939)148 that stabilized by the Axin2 protein, resulting in increased MBP expression and number of PLP+OLs in comparison of control group 9. Together, these studies demonstrate that both genetic and pharmacological activation of Wnt/β-catenin impair OPC differentiation, thereby preventing cells from maturing and producing myelin sheaths.

TCF7l2, important component of Wnt, also affects the differentiation of OPCs. Various studies suggest that β-catenin/TCF7l2 complex is inhibitory for OPC differentiation and subsequent myelination. Fancy et al described that Olig2-Cre/DA-Cat mice expressed TCF7L2, an important nuclear binding partner of β-catenin 48. Two other independent studies demonstrated that deletion of Tcf7l2 inhibited OPC differentiation in the spinal cord, suggesting that TCF7L2 is actually necessary for OPC differentiation (58, 136). From these studies it can be assumed that β-catenin may mediate its negative effect on OPC differentiation at least in part by recruiting TCF7L2 to regulate the transcription of important Wnt pathway target genes. Fancy et al demonstrated that Tcf7l2 is normally expressed in OLs during postnatal development but not in adulthood, potentially rendering constitutively active β-catenin ineffectual as the mice aged, and providing a potential mechanism for the delay but not complete block in OPC differentiation in the DA-cat mice 48.

Promoting Effect of Wnt on OPC Development

Although the inhibitory effects of Wnt signaling pathway on OPC differentiation are well accepted, however some studies conflict this inhibitory effect. Those researchers have described Wnt as a positive regulator of OPCs development. Tawk et al showed that addition of Wnt1 or Wnt3a in OPCs culture increased the expression of PLP+OLs by 3.5-fold and 2-fold, respectively 149. Fancy et al described that microarray profiling has shown up regulation of Wnt ligand and receptors in lesions of MS and MS animal models 48. Conditional knockout of β-catenin resulted in significantly decreased PLP+ and MPB+ OLs 150. Knocking down of β-catenin and TCF molecules (all four types) decreased PLP promoter gene activity by 70%, reciprocally over expression of β-catenin increased PLP promoter gene activity in OLs lineage cells 89, 149. Knockout of TCF4 caused a myelin deficient phenotype 136. Some other studies showed that in TCF4 knockdown mouses expression of PLP & MBP was undetectable in comparison to control, indicating that TCF4 is essential for oligodendrocytes lineage differentiation and maturation 58, 151. Microarray analysis of tissues from patients with multiple sclerosis revealed high expression of TCF4 in active lesion compared normal appearing white matter and silent chronic lesion 152.

From these controversial results described by various studies, it has been proposed that TCF7L2/β-catenin level must be tightly controlled for proper myelination 151. Therefore the extent to which an experimental model increases the level of intranuclear β-catenin correlates with the effect on OL maturation 151.

Wnt and OPCs Developmental Stage

Oligodendrocyte precursor cells (OPCs) are generated from progenitor zones in the forebrain beginning at various times during embryonic development 24. The mechanisms regulating the spatial and temporal production of OPCs have not been clearly elucidated. Sonic Hedgehog regulates the production of OPCs from ventral progenitor zones 25 while In the telencephalon Wnt signaling plays a prominent dorsalizing role 153, 154. Wnt signaling has been observed significantly decreased in the cortical progenitor domain at embryonic period when OPCs are generated 48, 58, 138. Langseth et al described that Wnt signaling negatively regulates the specification of OPCs from neural progenitors and that inhibition of Wnt signaling increased the production of OPCs in the cortex 155. Kessaris et al described that Wnt is very high in cortical progenitors at E17.5 (before cortical OPC production) and decreased by P5 when OPCs production is prominent 24. Wnt signalling via the canonical pathway is transiently activated in OPCs concurrently with the initiation of terminal differentiation. Both β-catenin activity and the expression of Tcf7l2 are subsequently down-regulated in mature oligodendrocytes 48, 136. Shimizu et al, described that addition of Wnt3a supernatant to CG4 cells (an OL progenitor strain) and to the dissociated primary cultured cells resulted in inhibition of differentiation step from OL progenitor to O4-positive stage 138. Deletion of the Wnt effector Tcf7l2 blocks oligodendrocyte differentiation 58, 136 . These results have potential relevance for remyelination in human disease given that Wnt signaling components are present in MS lesions, suggesting that dysregulated Wnt/β-catenin signaling could contribute to the lack of remyelination, often seen in this disease 48.

These findings indicate that Wnt negatively regulate the OPCs production 150 at early developmental stage but at later stage promotes the differentiation of already established OPCs 155, 156 and finally down regulated when oligodendrocytes becomes mature 157.

Wnt Intensity and OPCs Development

Along with activation of Wnt at various developmental stages, intensity of Wnt activation also plays an important role in oligodendrocytes development. During myelin formation, TCF7L2 must be associated with moderate level of β-catenin and either high or low levels of TCF7L2/β-catenin are detrimental for myelination. Either increased or decreased levels of TCF4/β-catenin expression have inhibitory effects on myelination process 151. Dai et al observed the decreased number of Olig1+ and Olig2+ cells in β-catenin activated mice (CatG/+) in comparison to control, and expression of Sox10 and PDGFRα was also impaired. Along with the number, distribution of these cells also affected, at E13.5 cells were only detected in the ventral ventricular zone of spinal cord, in contrary to their wide distribution in control tissues. Fancy et al also demonstrated that DA β-catenin signalling is sufficient to impede the remyelination process in mice. Similar results were obtained in mice lacking a copy of the β-catenin antagonist, APC. Together, these findings suggest that constitutive expression of β-catenin in OPCs correlates with a significant impairment of the remyelination process 48. On other hand β-catenin inactivation (CatL/L) resulted in increased production of precocious OPCs (E12.5) 150.

Conclusion

In summary, Wnt signaling cascade is a critical pathway involved in many developmental and disease processes. Wnt regulates the OPCs proliferation and differentiation. Inspite of widely accepted role of Wnt as inhibitory for OPCs proliferation and differentiation, recently evidences have emerged that Wnt enhances OPCs development. Wnt’s inhibitory or enhancing effect depends on developmental stage & intensity of activation. In early stages, Wnt inhibits the OPCs formation from neural progenitors and differentiation into immature OLs but in late stages Wnt plays a promoting role in differentiation and maturation of OLs. Further research is needed for better understanding the mechanism of Wnt signaling cascade through which it promotes OPCs proliferation and differentiation. It will also helps in proper targeting by therapeutic agents in demyelinating diseases of central nervous system.

Funding Source

The fundamental research fund for Shenzhen Science and Technology, research grant. Grant number: JCY20160531193951630

References

  1. 1.Chang A, Tourtellotte W W, Rudick R, Trapp B D. (2002) Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. The New England journal of medicine;. 346(3), 165-73.
  1. 2.Franklin R J. (2002) Why does remyelination fail in multiple sclerosis?. , Nature reviews Neuroscience; 3(9), 705-14.
  1. 3.Khwaja O, Volpe J J. (2008) Pathogenesis of cerebral white matter injury of prematurity. Archives of disease in childhood Fetal and neonatal edition;. 93(2), 153-61.
  1. 4.Woodward L J, Anderson P J, Austin N C, Howard K, Inder T E. (2006) Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. The New England journal of medicine;. 355(7), 685-94.
  1. 5.Crawford A H, Chambers C, Franklin R J. (2013) Remyelination: the true regeneration of the central nervous system. , Journal of comparative 149-2.
  1. 6.Fancy S P, Kotter M R, Harrington E P, Huang J K, Zhao C et al. (2010) Overcoming remyelination failure in multiple sclerosis and other myelin disorders. , Experimental neurology 225(1), 18-23.
  1. 7.Franklin R J, Goldman S A.Glia Disease and Repair-Remyelination. perspectives in biology. 2015;7(7):a020594
  1. 8.Hagemeier K, Bruck W, Kuhlmann T. (2012) Multiple sclerosis - remyelination failure as a cause of disease progression. , Histology and histopathology 27(3), 277-87.
  1. 9.Fancy S P, Harrington E P, Yuen T J, Silbereis J C, Zhao C et al. (2011) Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination. , Nature neuroscience 14(8), 1009-16.
  1. 10.Franklin R J, Ffrench-Constant C. (2008) Remyelination in the CNS: from biology to therapy. , Nature reviews Neuroscience 9(11), 839-55.
  1. 11.Kotter M R, Stadelmann C, Hartung H P. (2011) Enhancing remyelination in disease--can we wrap it up? Brain : a journal of neurology ;134(Pt7):. 1882-900.
  1. 12.Miller R H, Bai L. (2007) Cellular approaches for stimulating CNS remyelination. Regenerative medicine;. 2(5), 817-29.
  1. 13.Miron V E, Kuhlmann T, Antel J P. (2011) Cells of the oligodendroglial lineage, myelination, and remyelination. , Biochimica et biophysica acta 1812(2), 184-93.
  1. 14.Gibson E M, Purger D, Mount C W, Goldstein A K, Lin G L et al. (2014) Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain.Science(NewYork,NY). 344(6183), 1252304.
  1. 15.Sowell E R, Peterson B S, Thompson P M, Welcome S E, Henkenius A L et al. (2003) Mapping cortical change across the human life span. , Nature neuroscience 6(3), 309-15.
  1. 16.Wake H, Lee P R, Fields R D. (2011) Control of local protein synthesis and initial events in myelination by action potentials.Science(NewYork,NY). 333(6049), 1647-51.
  1. 17.Zalc B, Fields R D. (2000) Do Action Potentials Regulate Myelination? The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. 6(1), 5-13.
  1. 18.Taveggia C, Feltri M L, Wrabetz L. (2010) Signals to promote myelin formation and repair. , Nature reviews Neurology 6(5), 276-87.
  1. 19.Yamazaki Y, Hozumi Y, Kaneko K, Fujii S, Goto K et al. (2010) Oligodendrocytes: facilitating axonal conduction by more than myelination. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. 16(1), 11-8.
  1. 20.Rosenberg S S, Chan J R. (2009) Modulating myelination: knowing when to say Wnt. Genes and development. 23(13), 1487-93.
  1. 21.Miller R H. (1996) Oligodendrocyte origins. Trends in neurosciences ;19(3):. 92-6.
  1. 22.Cai J, Qi Y, Hu X, Tan M, Liu Z et al. (2005) Generation of oligodendrocyte precursor cells from mouse dorsal spinal cord independent of Nkx6 regulation and Shh signaling. , Neuron 45(1), 41-53.
  1. 23.Lu Q R, Sun T, Zhu Z, Ma N, Garcia M et al. (2002) Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. , Cell 109(1), 75-86.
  1. 24.Kessaris N, Fogarty M, Iannarelli P, Grist M, Wegner M et al. (2006) Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage. , Nature neuroscience 9(2), 173-9.
  1. 25.Richardson W D, Kessaris N, Pringle N. (2006) Oligodendrocyte wars. , Nature reviews Neuroscience 7(1), 11-8.
  1. 26.Rogister B, Belachew S, Moonen G. (1999) Oligodendrocytes: from development to demyelinated lesion repair. , Acta neurologica Belgica; 99(1), 32-9.
  1. 27.McMorris F A, McKinnon R D. (1996) Regulation of oligodendrocyte development and CNS myelination by growth factors: prospects for therapy of demyelinating disease. Brain pathology. , (Zurich, Switzerland); 6(3), 313-29.
  1. 28.Liu R, Cai J, Hu X, Tan M, Qi Y et al. (2003) Region-specific and stage-dependent regulation of Olig gene expression and oligodendrogenesis by Nkx6.1 homeodomain transcription factor. Development. , (Cambridge, England); 130(25), 6221-31.
  1. 29.Qi Y, Tan M, Hui C C, Qiu M. (2003) Gli2 is required for normal Shh signaling and oligodendrocyte development in the spinal cord. Molecular and cellular neurosciences.;. 23(3), 440-50.
  1. 30.Chong S Y, Rosenberg S S, Fancy S P, Zhao C, Shen Y A et al. (2012) Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination. Proceedings of the National Academy of Sciences of the United States of America.; 109(4), 1299-304.
  1. 31.Bansal R, Stefansson K, Pfeiffer S E. (1992) Proligodendroblast antigen (POA), a developmental antigen expressed by A007/O4-positive oligodendrocyte progenitors prior to the appearance of sulfatide and galactocerebroside. , Journal of neurochemistry; 58(6), 2221-9.
  1. 32.Pfeiffer S E, Warrington A E, Bansal R. (1993) The oligodendrocyte and its many cellular processes. Trends in cell biology;. 3(6), 191-7.
  1. 33.Bauer N G, Richter-Landsberg C, Ffrench-Constant C. (2009) Role of the oligodendroglial cytoskeleton in differentiation and myelination. , Glia; 57(16), 1691-705.
  1. 34.Emery B. (2010) Regulation of oligodendrocyte differentiation and myelination.Science(NewYork,NY);330(6005):. 779-82.
  1. 35.Kessaris N, Pringle N, Richardson W D. (2008) Specification of CNS glia from neural stem cells in the embryonic neuroepithelium. , Philosophical transactions of the Royal Society of London Series B, Biological sciences; 363(1489), 71-85.
  1. 36.Owen J P, Marco E J, Desai S, Fourie E, Harris J et al. (2013) Abnormal white matter microstructure in children with sensory processing disorders. NeuroImage Clinical;2:. 844-53.
  1. 37.Wu Y H, Gau S S, Lo Y C, Tseng W Y. (2014) White matter tract integrity of frontostriatal circuit in attention deficit hyperactivity disorder: association with attention performance and symptoms. Human brain mapping;. 35(1), 199-212.
  1. 38.Nery S, Wichterle H, Fishell G. (2001) Sonic hedgehog contributes to oligodendrocyte specification in the mammalian forebrain. Development. , (Cambridge, England); 128(4), 527-40.
  1. 39.Orentas D M, Hayes J E, Dyer K L, Miller R H. (1999) Sonic hedgehog signaling is required during the appearance of spinal cord oligodendrocyte precursors. Development. , (Cambridge, England); 126(11), 2419-29.
  1. 40.Barres B A, Lazar M A, Raff M C. (1994) A novel role for thyroid hormone, glucocorticoids and retinoic acid in timing oligodendrocyte development. Development. , (Cambridge, England); 120(5), 1097-108.
  1. 41.Pombo P M, Barettino D, Ibarrola N, Vega S, Rodriguez-Pena A. (1999) Stimulation of the myelin basic protein gene expression by 9-cis-retinoic acid and thyroid hormone: activation in the context of its native promoter. Brain research Molecular brain research;. 64(1), 92-100.
  1. 42.Back S A, Craig A, Kayton R J, Luo N L, Meshul C K et al. (2007) Hypoxia-ischemia preferentially triggers glutamate depletion from oligodendroglia and axons in perinatal cerebral white matter. , Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism; 27(2), 334-47.
  1. 43.Mason J L, Ye P, Suzuki K, D'Ercole A J, Matsushima G K. (2000) Insulin-like growth factor-1 inhibits mature oligodendrocyte apoptosis during primary demyelination. , The Journal of neuroscience : the official journal of the Society for 20(15), 5703-8.
  1. 44.Huang J K, Jarjour A A, Nait Oumesmar B, Kerninon C, Williams A et al. (2011) Retinoid X receptor gamma signaling accelerates CNS remyelination. , Nature neuroscience; 14(1), 45-53.
  1. 45.Fortin D, Rom E, Sun H, Yayon A, Bansal R. (2005) Distinct fibroblast growth factor (FGF)/FGF receptor signaling pairs initiate diverse cellular responses in the oligodendrocyte lineage. , The Journal of neuroscience : the official journal of the Society for Neuroscience; 25(32), 7470-9.
  1. 46.Baron W, Metz B, Bansal R, Hoekstra D, H de Vries. (2000) PDGF and FGF-2 signaling in oligodendrocyte progenitor cells: regulation of proliferation and differentiation by multiple intracellular signaling pathways. Molecular and cellular neurosciences;. 15(3), 314-29.
  1. 47.Zhou Y X, Armstrong R C. (2007) Interaction of fibroblast growth factor 2 (FGF2) and notch signaling components in inhibition of oligodendrocyte progenitor (OP) differentiation. , Neuroscience letters; 421(1), 27-32.
  1. 48.Fancy S P, Baranzini S E, Zhao C, Yuk D I, Irvine K A et al. (2009) Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS. Genes and development;. 23(13), 1571-85.
  1. 49.Feigenson K, Reid M, See J, Crenshaw I E, Grinspan J B. (2011) Canonical Wnt signalling requires the BMP pathway to inhibit oligodendrocyte maturation. 3(3), 00061.
  1. 50.Wang S, Sdrulla A D, diSibio G, Bush G, Nofziger D et al. (1998) Notch receptor activation inhibits oligodendrocyte differentiation. , Neuron; 21(1), 63-75.
  1. 51.Zhang Y, Argaw A T, Gurfein B T, Zameer A, Snyder B J et al. (2009) Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination. Proceedings of the National Academy of Sciences of the United States of America 106(45), 19162-7.
  1. 52.Gomes W A, Mehler M F, Kessler J A. (2003) Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment. Developmental biology. 255(1), 164-77.
  1. 53.Grinspan J B, Edell E, Carpio D F, Beesley J S, Lavy L et al. (2000) Stage-specific effects of bone morphogenetic proteins on the oligodendrocyte lineage. , Journal of neurobiology 43(1), 1-17.
  1. 54.See J, Zhang X, Eraydin N, Mun S B, Mamontov P et al. (2004) Oligodendrocyte maturation is inhibited by bone morphogenetic protein. Molecular and cellular neurosciences. 26(4), 481-92.
  1. 55.Sim F J, Lang J K, Waldau B, Roy N S, Schwartz T E et al. (2006) Complementary patterns of gene expression by human oligodendrocyte progenitors and their environment predict determinants of progenitor maintenance and differentiation. Annals of neurology. 59(5), 763-79.
  1. 56.Peters A, Sethares C. (2004) Oligodendrocytes, their progenitors and other neuroglial cells in the aging primate cerebral cortex. Cerebral cortex. , New York, NY : 14(9), 995-1007.
  1. 57.Menn B, Garcia-Verdugo J M, Yaschine C, Gonzalez-Perez O, Rowitch D et al. (2006) Origin of oligodendrocytes in the subventricular zone of the adult brain. , The Journal of neuroscience : the official journal of the Society for Neuroscience 26(30), 7907-18.
  1. 58.Ye F, Chen Y, Hoang T, Montgomery R L, Zhao X H et al. (2009) HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the beta-catenin-TCF interaction. , Nature 12(7), 829-38.
  1. 59.Shen S, Sandoval J, Swiss V A, Li J, Dupree J et al. (2008) Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. , Nature 11(9), 1024-34.
  1. 60.Shen S, Li J, Casaccia-Bonnefil P. (2005) Histone modifications affect timing of oligodendrocyte progenitor differentiation in the developing rat brain. The Journal of cell biology. 169(4), 577-89.
  1. 61.Liu J, Sandoval J, Doh S T, Cai L, Lopez-Rodas G et al. (2010) Epigenetic modifiers are necessary but not sufficient for reprogramming non-myelinating cells into myelin gene-expressing cells. PloS one ;5(9):e13023.
  1. 62.Liu A, Li J, Marin-Husstege M, Kageyama R, Fan Y et al. (2006) A molecular insight of Hes5-dependent inhibition of myelin gene expression: old partners and new players. The EMBO journal. 25(20), 4833-42.
  1. 63.R van Amerongen, Nusse R. (2009) Towards an integrated view of Wnt signaling in development. Development. , (Cambridge, England) 136(19), 3205-14.
  1. 64.Logan C Y, Nusse R. (2004) The Wnt signaling pathway in development and disease. Annual review of cell and developmental biology. 20, 781-810.
  1. 65.Clevers H. (2006) Wnt/beta-catenin signaling in development and disease. , Cell 127(3), 469-80.
  1. 66.Song J L, Nigam P, Tektas S S, Selva E. (2015) microRNA regulation of Wnt signaling pathways in development and disease. Cellular signalling. 27(7), 1380-91.
  1. 67.Kuhl M, Sheldahl L C, Park M, Miller J R, Moon R T. (2000) The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape. Trends in genetics :. , TIG 16(7), 279-83.
  1. 68.Fiedler M, Mendoza-Topaz C, Rutherford T J, Mieszczanek J, Bienz M. (2011) Dishevelled interacts with the DIX domain polymerization interface of Axin to interfere with its function in down-regulating beta-catenin. Proceedings of the National Academy of Sciences of the United States of America 108(5), 1937-42.
  1. 69.Clevers H, Nusse R. (2012) Wnt/beta-catenin signaling and disease. , Cell 149(6), 1192-205.
  1. 70.Peng Y, Zhang X, Feng X, Fan X, Jin Z.The crosstalk between microRNAs and the Wnt/beta-catenin signaling pathway in cancer. Oncotarget.2016 .
  1. 71.He X, Semenov M, Tamai K, Zeng X. (2004) LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development (Cambridge. , England) 131(8), 1663-77.
  1. 72.Willert K, Brown J D, Danenberg E, Duncan A W, Weissman I L et al. (2003) Wnt proteins are lipid-modified and can act as stem cell growth factors. , Nature 423(6938), 448-52.
  1. 73.Binnerts M E, Kim K A, Bright J M, Patel S M, Tran K et al. (2007) R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6. Proceedings of the National Academy of Sciences of the United States of America 104(37), 14700-5.
  1. 74.Bryja V, Andersson E R, Schambony A, Esner M, Bryjova L et al. (2009) The extracellular domain of Lrp5/6 inhibits noncanonical Wnt signaling in vivo. Molecular biology of the cell. 20(3), 924-36.
  1. 75.Tahinci E, Thorne C A, Franklin J L, Salic A, Christian K M et al. (2007) Lrp6 is required for convergent extension during Xenopus gastrulation. Development (Cambridge. , England) 134(22), 4095-106.
  1. 76.Bovolenta P, Esteve P, Ruiz J M, Cisneros E, Lopez-Rios J. (2008) Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease. , Journal of cell 121, 737-46.
  1. 77.Mao B, Wu W, Davidson G, Marhold J, Li M et al. (2002) Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. , Nature 417(6889), 664-7.
  1. 78.Semenov M V, Tamai K, Brott B K, Kuhl M, Sokol S et al. (2001) . Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Current biology : CB 11(12), 951-61.
  1. 79.Ellwanger K, Saito H, Clement-Lacroix P, Maltry N, Niedermeyer J et al. (2008) Targeted disruption of the Wnt regulator Kremen induces limb defects and high bone density. Molecular and cellular biology. 28(15), 4875-82.
  1. 80.Semenov M, Tamai K, He X. (2005) SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. , The Journal of biological chemistry 280(29), 26770-5.
  1. 81.Yamamoto A, Nagano T, Takehara S, Hibi M, Aizawa S. (2005) Shisa promotes head formation through the inhibition of receptor protein maturation for the caudalizing factors. , Wnt and FGF Cell 120(2), 223-35.
  1. 82.Zhu W, Shiojima I, Ito Y, Li Z, Ikeda H et al. (2008) IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis. , Nature 454(7202), 345-9.
  1. 83.Xu Q, Wang Y, Dabdoub A, Smallwood P M, Williams J et al. (2004) Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. , Cell 116(6), 883-95.
  1. 84.Kazanskaya O, Glinka A, I del Barco Barrantes, Stannek P, Niehrs C et al. (2004) R-Spondin2 is a secreted activator of Wnt/beta-catenin signaling and is required for Xenopus myogenesis. Developmental cell. 7(4), 525-34.
  1. 85.Kim K A, Kakitani M, Zhao J, Oshima T, Tang T et al. (2005) . Mitogenic influence of human R-spondin1 on the intestinal epithelium. Science , (New York, NY) 309(5738), 1256-9.
  1. 86.Nam J S, Turcotte T J, Smith P F, Choi S, Yoon J K. (2006) Mouse cristin/R-spondin family proteins are novel ligands for the Frizzled 8 and LRP6 receptors and activate beta-catenin-dependent gene expression. The Journal of biological chemistry. 281(19), 13247-57.
  1. 87.Wei Q, Yokota C, Semenov M V, Doble B, Woodgett J et al. (2007) R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and beta-catenin signaling. The Journal of biological chemistry. 282(21), 15903-11.
  1. 88.Bell S M, Schreiner C M, Wert S E, Mucenski M L, Scott W J et al. (2008) R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis. Development (Cambridge. , England) 135(6), 1049-58.
  1. 89.Morin P J. (1999) beta-catenin signaling and cancer. BioEssays : news and reviews in molecular, cellular and developmental biology. 21(12), 1021-30.
  1. 90.Kimelman D, Xu W. (2006) beta-catenin destruction complex: insights and questions from a structural perspective. , Oncogene 25(57), 7482-91.
  1. 91.Arce L, Yokoyama N N, Waterman M L. (2006) Diversity of LEF/TCF action in development and disease. , Oncogene 25(57), 7492-504.
  1. 92.Hoppler S, Kavanagh C L. (2007) Wnt signalling: variety at the core. , Journal of cell 120, 385-93.
  1. 93.Daniels D L, Weis W I. (2005) Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation. Nature structural & molecular biology. 12(4), 364-71.
  1. 94.Hatzis P, LG van der Flier, van Driel MA, Guryev V, Nielsen F et al. (2008) Genome-wide pattern of TCF7L2/TCF4 chromatin occupancy in colorectal cancer cells. Molecular and cellular biology. 28(8), 2732-44.
  1. 95.Atcha F A, Syed A, Wu B, Hoverter N P, Yokoyama N N et al. (2007) A unique DNA binding domain converts T-cell factors into strong Wnt effectors. Molecular and cellular biology. 27(23), 8352-63.
  1. 96.Li J, Wang C Y. (2008) TBL1-TBLR1 and beta-catenin recruit each other to Wnt target-gene promoter for transcription activation and oncogenesis. Nature cell biology. 10(2), 160-9.
  1. 97.Tago K, Nakamura T, Nishita M, Hyodo J, Nagai S et al. (2000) Inhibition of Wnt signaling by ICAT, a novel beta-catenin-interacting protein. , Genes & development 14(14), 1741-9.
  1. 98.Zhang W, Chen X, Kato Y, Evans P M, Yuan S et al. (2006) Novel cross talk of Kruppel-like factor 4 and beta-catenin regulates normal intestinal homeostasis and tumor repression. Molecular and cellular biology. 26(6), 2055-64.
  1. 99.Vlad A, Rohrs S, Klein-Hitpass L, Muller O. (2008) The first five years of the Wnt targetome. Cellular signalling. 20(5), 795-802.
  1. 100.Chamorro M N, Schwartz D R, Vonica A, Brivanlou A H, Cho K R et al. (2005) FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development. The EMBO journal. 24(1), 73-84.
  1. 101.Khan Z, Vijayakumar S, TV de la Torre, Rotolo S, Bafico A. (2007) Analysis of endogenous LRP6 function reveals a novel feedback mechanism by which Wnt negatively regulates its receptor. Molecular and cellular biology. 27(20), 7291-301.
  1. 102.Mosimann C, Hausmann G, Basler K. (2009) Beta-catenin hits chromatin: regulation of Wnt target gene activation. Nature reviews Molecular cell biology. 10(4), 276-86.
  1. 103.Willert K, Jones K A. (2006) Wnt signaling: is the party in the nucleus?. , Genes & 20(11), 1394-404.
  1. 104.Parma P, Radi O, Vidal V, Chaboissier M C, Dellambra E et al. (2006) R-spondin1 is essential in sex determination, skin differentiation and malignancy. , Nature 38(11), 1304-9.
  1. 105.Biason-Lauber A, Konrad D, Navratil F, Schoenle E J. (2004) A WNT4 mutation associated with Mullerian-duct regression and virilization in a 46,XX woman. The New England journal of medicine. 351(8), 792-8.
  1. 106.Toomes C, Bottomley H M, Jackson R M, Towns K V, Scott S et al. (2004) Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. American journal of human genetics. 74(4), 721-30.
  1. 107.Gong Y, Slee R B, Fukai N, Rawadi G, Roman-Roman S et al. (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. , Cell 107(4), 513-23.
  1. 108.Boyden L M, Mao J, Belsky J, Mitzner L, Farhi A et al. (2002) High bone density due to a mutation in LDL-receptor-related protein 5. The New England journal of medicine. 346(20), 1513-21.
  1. 109.Little R D, Carulli J P, Del Mastro RG, Dupuis J, Osborne M et al. (2002) A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. American journal of human genetics. 70(1), 11-9.
  1. 110.Grant S F, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A et al. (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. , Nature 38(3), 320-3.
  1. 111.Welters H J, Kulkarni R N. (2008) Wnt signaling: relevance to beta-cell biology and diabetes. Trends in endocrinology and metabolism:. 19(10), 349-55.
  1. 112.Polakis P. (2007) The many ways of Wnt in cancer. Current opinion in genetics & development 17(1), 45-51.
  1. 113.Fuchs E. (2009) The tortoise and the hair: slow-cycling cells in the stem cell race. , Cell 137(5), 811-9.
  1. 114.Qi Y, Cai J, Wu Y, Wu R, Lee J et al. (2001) Control of oligodendrocyte differentiation by the Nkx2.2 homeodomain transcription factor. Development (Cambridge. , England) 128(14), 2723-33.
  1. 115.Davies J E, Miller R H. (2001) Local sonic hedgehog signaling regulates oligodendrocyte precursor appearance in multiple ventricular zone domains in the chick metencephalon. Developmental biology. 233(2), 513-25.
  1. 116.Yung S Y, Gokhan S, Jurcsak J, Molero A E, Abrajano J J et al. (2002) Differential modulation of BMP signaling promotes the elaboration of cerebral cortical GABAergic neurons or oligodendrocytes from a common sonic hedgehog-responsive ventral forebrain progenitor species. Proceedings of the National Academy of Sciences of the United States of America 99(25), 16273-8.
  1. 117.Wada T, Kagawa T, Ivanova A, Zalc B, Shirasaki R et al. (2000) Dorsal spinal cord inhibits oligodendrocyte development. Developmental biology. 227(1), 42-55.
  1. 118.Samanta J, Kessler J A. (2004) Interactions between ID and OLIG proteins mediate the inhibitory effects of BMP4 on oligodendroglial differentiation. Development (Cambridge. , England) 131(17), 4131-42.
  1. 119.Miller R H, Dinsio K, Wang R, Geertman R, Maier C E et al. (2004) Patterning of spinal cord oligodendrocyte development by dorsally derived BMP4. , Journal of neuroscience research 76(1), 9-19.
  1. 120.Nohe A, Keating E, Knaus P, Petersen N O. (2004) Signal transduction of bone morphogenetic protein receptors. Cellular signalling. 16(3), 291-9.
  1. 121.Liu A, Niswander L A. (2005) Bone morphogenetic protein signalling and vertebrate nervous system development. , Nature reviews Neuroscience 6(12), 945-54.
  1. 122.Janknecht R, Wells N J, Hunter T. (1998) TGF-beta-stimulated cooperation of smad proteins with the coactivators. CBP/p300. Genes & development 12(14), 2114-9.
  1. 123.Feng X H, Zhang Y, Wu R Y, Derynck R. (1998) The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation. , Genes & development 12(14), 2153-63.
  1. 124.Yokota Y. (2001) Id and development. , Oncogene 20(58), 8290-8.
  1. 125.Wang S, Sdrulla A, Johnson J E, Yokota Y, Barres B A. (2001) A role for the helix-loop-helix protein Id2 in the control of oligodendrocyte development. , Neuron 29(3), 603-14.
  1. 126.Rivera R, Murre C. (2001) The regulation and function of the Id proteins in lymphocyte development. , Oncogene 20(58), 8308-16.
  1. 127.Kondo T. (2009) [Common mechanism underlying oligodendrocyte development and oligodendrogliomagenesis]. Brain and nerve = Shinkei kenkyu no shinpo. 61(7), 741-51.
  1. 128.Rios I, Alvarez-Rodriguez R, Marti E, Pons S. (2004) Bmp2 antagonizes sonic hedgehog-mediated proliferation of cerebellar granule neurones through. Smad5 signalling. Development , (Cambridge, England) 131(13), 3159-68.
  1. 129.Mekki-Dauriac S, Agius E, Kan P, Cochard P. (2002) Bone morphogenetic proteins negatively control oligodendrocyte precursor specification in the chick spinal cord. Development (Cambridge. , England) 129(22), 5117-30.
  1. 130.Colak D, Mori T, Brill M S, Pfeifer A, Falk S et al. (2008) Adult neurogenesis requires Smad4-mediated bone morphogenic protein signaling in stem cells. , The Journal of neuroscience : the official journal of the Society for Neuroscience 28(2), 434-46.
  1. 131.Deininger M, Meyermann R, Schluesener H. (1995) Detection of two transforming growth factor-beta-related morphogens, bone morphogenetic proteins-4 and -5, in RNA of multiple sclerosis and Creutzfeldt-Jakob disease lesions. Acta neuropathologica. 90(1), 76-9.
  1. 132.Wang Y, Cheng X, He Q, Zheng Y, Kim D H et al. (2011) Astrocytes from the contused spinal cord inhibit oligodendrocyte differentiation of adult oligodendrocyte precursor cells by increasing the expression of bone morphogenetic proteins. The Journal of neuroscience : the official journal of the Society for Neuroscience. 31(16), 6053-8.
  1. 133.Ara J, See J, Mamontov P, Hahn A, Bannerman P et al. (2008) Bone morphogenetic proteins 4, 6, and 7 are up-regulated in mouse spinal cord during experimental autoimmune encephalomyelitis. , Journal of neuroscience research 86(1), 125-35.
  1. 134.Cate H S, Sabo J K, Merlo D, Kemper D, Aumann T D et al. (2010) Modulation of bone morphogenic protein signalling alters numbers of astrocytes and oligodendroglia in the subventricular zone during cuprizone-induced demyelination. , Journal of neurochemistry 115(1), 11-22.
  1. 135.Sabo J K, Aumann T D, Merlo D, Kilpatrick T J, Cate H S. (2011) Remyelination is altered by bone morphogenic protein signaling in demyelinated lesions. , The Journal of neuroscience : the official journal of the Society for Neuroscience 31(12), 4504-10.
  1. 136.Fu H, Cai J, Clevers H, Fast E, Gray S et al. (2009) A genome-wide screen for spatially restricted expression patterns identifies transcription factors that regulate glial development. , The Journal of neuroscience : the official journal of the Society for Neuroscience 29(36), 11399-408.
  1. 137.Zhou Q, Choi G, Anderson D J. (2001) The bHLH transcription factor Olig2 promotes oligodendrocyte differentiation in collaboration with Nkx2.2. , Neuron 31(5), 791-807.
  1. 138.Shimizu T, Kagawa T, Wada T, Muroyama Y, Takada S et al. (2005) Wnt signaling controls the timing of oligodendrocyte development in the spinal cord. Developmental biology. 282(2), 397-410.
  1. 139.Feigenson K, Reid M, See J, Crenshaw E B, Grinspan JB 3rd. (2009) Wnt signaling is sufficient to perturb oligodendrocyte maturation. Molecular and cellular neurosciences. 42(3), 255-65.
  1. 140.Azim K, Butt A M. (2011) GSK3beta negatively regulates oligodendrocyte differentiation and myelination in vivo. , Glia 59(4), 540-53.
  1. 141.Lee H K, Laug D, Zhu W, Patel J M, Ung K et al. (2015) Apcdd1 stimulates oligodendrocyte differentiation after white matter injury. , Glia 63(10), 1840-9.
  1. 142.Lee H K, Deneen B. (2012) Daam2 is required for dorsal patterning via modulation of canonical Wnt signaling in the developing spinal cord. Developmental cell. 22(1), 183-96.
  1. 143.Lee H K, Chaboub L S, Zhu W, Zollinger D, Rasband M N et al. (2015) Daam2-PIP5K is a regulatory pathway for Wnt signaling and therapeutic target for remyelination in the CNS. , Neuron 85(6), 1227-43.
  1. 144.Behrens J, Jerchow B A, Wurtele M, Grimm J, Asbrand C et al. (1998) Functional interaction of an axin homolog, conductin. with beta-catenin, APC, and GSK3beta. Science , (New York, NY) 280(5363), 596-9.
  1. 145.Jho E H, Zhang T, Domon C, Joo C K, Freund J N et al. (2002) Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Molecular and cellular biology. 22(4), 1172-83.
  1. 146.Lang J, Maeda Y, Bannerman P, Xu J, Horiuchi M et al. (2013) Adenomatous polyposis coli regulates oligodendroglial development. , The Journal of neuroscience : the official journal of the Society for Neuroscience 33(7), 3113-30.
  1. 147.Zeng Y A, Nusse R. (2010) Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell stem cell. 6(6), 568-77.
  1. 148.Huang S M, Mishina Y M, Liu S, Cheung A, Stegmeier F et al. (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. , Nature 461(7264), 614-20.
  1. 149.Tawk M, Makoukji J, Belle M, Fonte C, Trousson A et al. (2011) Wnt/beta-catenin signaling is an essential and direct driver of myelin gene expression and myelinogenesis. , The Journal of neuroscience : the official journal of the Society for Neuroscience 31(10), 3729-42.
  1. 150.Dai Z M, Sun S, Wang C, Huang H, Hu X et al. (2014) Stage-specific regulation of oligodendrocyte development by Wnt/beta-catenin signaling. , The Journal of neuroscience : the official journal of the Society for Neuroscience 34(25), 8467-73.
  1. 151.Fu H, Kesari S, Cai J. (2012) Tcf7l2 is tightly controlled during myelin formation. Cellular and molecular neurobiology. 32(3), 345-52.
  1. 152.Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E et al. (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. , Nature medicine 8(5), 500-8.
  1. 153.Kim A S, Lowenstein D H, Pleasure S J. (2001) Wnt receptors and Wnt inhibitors are expressed in gradients in the developing telencephalon. Mechanisms of development. 103-1.
  1. 154.Lee S M, Tole S, Grove E, McMahon A P. (2000) A local Wnt-3a signal is required for development of the mammalian hippocampus. Development (Cambridge. , England) 127(3), 457-67.
  1. 155.Langseth A J, Munji R N, Choe Y, Huynh T, Pozniak C D et al. (2010) Wnts influence the timing and efficiency of oligodendrocyte precursor cell generation in the telencephalon. , The Journal of neuroscience : the official journal of the Society for Neuroscience 30(40), 13367-72.
  1. 156.White B D, Nathe R J, Maris D O, Nguyen N K, Goodson J M et al. (2010) Beta-catenin signaling increases in proliferating NG2+ progenitors and astrocytes during post-traumatic gliogenesis in the adult brain. Stem cells. , (Dayton, Ohio) 28(2), 297-307.
  1. 157.Fu H, Qi Y, Tan M, Cai J, Takebayashi H et al. (2002) Dual origin of spinal oligodendrocyte progenitors and evidence for the cooperative role of. Olig2 and Nkx2.2 in the control of oligodendrocyte differentiation. Development , (Cambridge, England) 129(3), 681-93.
  1. 158.Niemann S, Zhao C, Pascu F, Stahl U, Aulepp U et al. (2004) Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family. American journal of human genetics. 74(3), 558-63.
  1. 159.Kanazawa A, Tsukada S, Sekine A, Tsunoda T, Takahashi A et al. (2004) Association of the gene encoding wingless-type mammary tumor virus integration-site family member 5B (WNT5B) with type 2 diabetes. American journal of human genetics. 75(5), 832-43.
  1. 160.Woods C G, Stricker S, Seemann P, Stern R, Cox J et al. (2006) Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. American journal of human genetics. 79(2), 402-8.
  1. 161.Adaimy L, Chouery E, Megarbane H, Mroueh S, Delague V et al. (2007) Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia. American journal of human genetics. 81(4), 821-8.
  1. 162.Christodoulides C, Scarda A, Granzotto M, Milan G, Dalla Nora E et al. (2006) WNT10B mutations in human obesity. , Diabetologia 49(4), 678-84.
  1. 163.Bergmann C, Senderek J, Anhuf D, Thiel C T, Ekici A B et al. (2006) Mutations in the gene encoding the Wnt-signaling component R-spondin 4 (RSPO4) cause autosomal recessive anonychia. American journal of human genetics. 79(6), 1105-9.
  1. 164.Balemans W, Patel N, Ebeling M, E Van Hul, Wuyts W et al. (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. , Journal of medical genetics 39(2), 91-7.
  1. 165.Bjorklund P, Akerstrom G, Westin G. (2007) An LRP5 receptor with internal deletion in hyperparathyroid tumors with implications for deregulated WNT/beta-catenin signaling. PLoS medicine.;4(11):e328.
  1. 166.Mani A, Radhakrishnan J, Wang H, Mani A, Mani M A et al. (2007) LRP6 mutation in a family with early coronary disease and metabolic risk factors.Science(New. , York, NY) 315(5816), 1278-82.
  1. 167.Robitaille J, MacDonald M L, Kaykas A, Sheldahl L C, Zeisler J et al. (2002) Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. , Nature 32(2), 326-30.
  1. 168.Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N et al. (2000) AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. , Nature 24(3), 245-50.
  1. 169.Oates N A, J van Vliet, Duffy D L, Kroes H Y, Martin N G et al. (2006) Increased DNA methylation at the AXIN1 gene in a monozygotic twin from a pair discordant for a caudal duplication anomaly. American journal of human genetics. 79(1), 155-62.
  1. 170.Liu W, Dong X, Mai M, Seelan R S, Taniguchi K et al. (2000) Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling. , Nature 26(2), 146-7.
  1. 171.Lammi L, Arte S, Somer M, Jarvinen H, Lahermo P et al. (2004) Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. American journal of human genetics. 74(5), 1043-50.
  1. 172.Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H et al. (1991) . Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science , (New York, NY) 253(5020), 665-9.
  1. 173.Kinzler K W, Nilbert M C, Vogelstein B, Bryan T M, Levy D B et al. (1991) Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. , (New York, NY) 251(4999), 1366-70.
  1. 174.Rivera M N, Kim W J, Wells J, Driscoll D R, Brannigan B W et al. (2007) An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. , (New York, NY) 315(5812), 642-5.
  1. 175.Major M B, Camp N D, Berndt J D, Yi X, Goldenberg S J et al. (2007) Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling. , (New York, NY) 316(5827), 1043-6.
  1. 176.Morin P J, Sparks A B, Korinek V, Barker N, Clevers H et al. (1997) Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. , (New York, NY) 275(5307), 1787-90.
  1. 177.Korinek V, Barker N, Morin P J, D van Wichen, R de Weger et al. (1997) Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. , (New York, NY) 275(5307), 1784-7.
  1. 178.Florez J C, Jablonski K A, Bayley N, Pollin T I, de Bakker PI et al. (2006) TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. The New England journal of medicine. 355(3), 241-50.

Cited by (11)

  1. 1.Namvarpour Zahra, Ranaei Elahe, Amini Abdollah, Roudafshani Zahra, Fahanik-Babaei Javad, 2022, Effects of prenatal exposure to inflammation coupled with prepubertal stress on prefrontal white matter structure and related molecules in adult mouse offspring, Metabolic Brain Disease, 37(5), 1655, 10.1007/s11011-022-00968-9
  1. 2.Manukjan Narek, Ahmed Zubair, Fulton Daniel, Blankesteijn W. Matthijs, Foulquier Sébastien, 2020, A Systematic Review of WNT Signaling in Endothelial Cell Oligodendrocyte Interactions: Potential Relevance to Cerebral Small Vessel Disease, Cells, 9(6), 1545, 10.3390/cells9061545
  1. 3.Imani Seyedeh Zahra Hosseini, Hojati Zohreh, Khalilian Sheyda, Dehghanian Fariba, Kheirollahi Majid, et al, 2021, Expression and clinical significance of IL7R, NFATc2, and RNF213 in familial and sporadic multiple sclerosis, Scientific Reports, 11(1), 10.1038/s41598-021-98691-5
  1. 4.Reiche Laura, Küry Patrick, Göttle Peter, 2019, Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?, Cells, 8(12), 1591, 10.3390/cells8121591
  1. 5.Kiaie Nasim, Gorabi Armita Mahdavi, Loveless Reid, Teng Yong, Jamialahmadi Tannaz, et al, 2022, The regenerative potential of glial progenitor cells and reactive astrocytes in CNS injuries, Neuroscience & Biobehavioral Reviews, 140(), 104794, 10.1016/j.neubiorev.2022.104794
  1. 6.Tan Rui, Hong Rui, Sui Chunxiao, Yang Dianxu, Tian Hengli, et al, 2023, The role and potential therapeutic targets of astrocytes in central nervous system demyelinating diseases, Frontiers in Cellular Neuroscience, 17(), 10.3389/fncel.2023.1233762
  1. 7.Lorenzati Martina, Boda Enrica, Parolisi Roberta, Bonato Martino, Borsello Tiziana, et al, 2021, c-Jun N-terminal kinase 1 (JNK1) modulates oligodendrocyte progenitor cell architecture, proliferation and myelination, Scientific Reports, 11(1), 10.1038/s41598-021-86673-6
  1. 8.Namvarpour Zahra, Afsordeh Kobra, Amini Abdollah, Fathabady Fatemeh Fadaei, 2021, Alpha lipoic acid ameliorates detrimental effects of maternal lipopolysaccharides exposure on prefrontal white matter in adult male offspring rats, Journal of Chemical Neuroanatomy, 118(), 102038, 10.1016/j.jchemneu.2021.102038
  1. 9.Ruzha Yelizhati, Ni Junjun, Quan Zhenzhen, Li Hui, Qing Hong, 2022, Role of Vitronectin and Its Receptors in Neuronal Function and Neurodegenerative Diseases, International Journal of Molecular Sciences, 23(20), 12387, 10.3390/ijms232012387
  1. 10.Sokol Deborah K., Lahiri Debomoy K., 2023, APPlications of amyloid-β precursor protein metabolites in macrocephaly and autism spectrum disorder, Frontiers in Molecular Neuroscience, 16(), 10.3389/fnmol.2023.1201744
  1. 11.Pooyan Paria, Karamzadeh Razieh, Mirzaei Mehdi, Meyfour Anna, Amirkhan Ardeshir, et al, 2020, The Dynamic Proteome of Oligodendrocyte Lineage Differentiation Features Planar Cell Polarity and Macroautophagy Pathways, GigaScience, 9(11), 10.1093/gigascience/giaa116