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Developmental Cues and Molecular Drivers in Myelinogenesis: Revisiting Early Life to Re-Evaluate the Integrity of CNS Myelin

Iasonas Dermitzakis
Maria Eleni Manthou
Soultana Meditskou
Dimosthenis Miliaras
Evangelia Kesidou
Marina Boziki
Steven Petratos
Nikolaos Grigoriadis
2 and
Paschalis Theotokis
Department of Histology-Embryology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Laboratory of Experimental Neurology and Neuroimmunology, Second Department of Neurology, AHEPA University Hospital, 54621 Thessaloniki, Greece
Department of Neuroscience, Central Clinical School, Monash University, Prahran, VIC 3004, Australia
Author to whom correspondence should be addressed.
Curr. Issues Mol. Biol. 2022, 44(7), 3208-3237;
Submission received: 30 June 2022 / Revised: 14 July 2022 / Accepted: 17 July 2022 / Published: 19 July 2022


The mammalian central nervous system (CNS) coordinates its communication through saltatory conduction, facilitated by myelin-forming oligodendrocytes (OLs). Despite the fact that neurogenesis from stem cell niches has caught the majority of attention in recent years, oligodendrogenesis and, more specifically, the molecular underpinnings behind OL-dependent myelinogenesis, remain largely unknown. In this comprehensive review, we determine the developmental cues and molecular drivers which regulate normal myelination both at the prenatal and postnatal periods. We have indexed the individual stages of myelinogenesis sequentially; from the initiation of oligodendrocyte precursor cells, including migration and proliferation, to first contact with the axon that enlists positive and negative regulators for myelination, until the ultimate maintenance of the axon ensheathment and myelin growth. Here, we highlight multiple developmental pathways that are key to successful myelin formation and define the molecular pathways that can potentially be targets for pharmacological interventions in a variety of neurological disorders that exhibit demyelination.

1. Introduction

As the regulator of all cognitive, sensory, and motor activity, the nervous system is the most complex biological system in humans; the complexities of integrated neural networks are a hot area of intensive research that will require multidisciplinary investigations to address a variable array of neurological disorders that remain an unmet medical need. The main types of cells in the nervous system are neurons and glial cells with the latter performing vital supporting roles [1,2]. The glial/neuronal ratio differs uniformly across brain regions of mammalian species, underlining the pivotal role of interaction between glial cells and neurons for appropriate integration of the central nervous system (CNS) to coordinate neurophysiological and cognitive functions [3]. For propagation of action potentials to ensue in neurons, axonal myelination is crucial [4,5]. The cells responsible for myelination are the oligodendrocytes (OLs) in the CNS and Schwann cells in the peripheral nervous system (PNS). Rudolf Virchow initially designated the term “myelin” in 1854, named after the Greek word “marrow” (myelos), since it is especially plentiful in the brain’s center, or marrow [6]. He posited that neurons produced myelin, but Pío del Río Hortega’s better histological staining processes almost a century ago revealed that myelin is created by specific glial cells, which are OLs [7,8].
The CNS macroglia and neurons have a common embryonic origin from the neuroectoderm, most prominently from neuroepithelial cells of the telencephalic ventricular and subventricular zone (VZ and SVZ), while the spinal cord is supplied with cell derivatives exclusively from the central canal [9,10]. Newborn CNS is radically unmyelinated with a sparse developing pool of unipotent cells, namely oligodendrocyte precursor cells (OPCs), following their birth with gradual widespread functionality in the first few years of childhood [11]. Myelination persists in an asynchronous spatiotemporal pattern through adolescence towards adulthood, coinciding with the establishment and maintenance of correct circuit function and cognitive development [12,13]. Mature myelin sheaths remain stable by and large; however, they maintain the capacity to remodel and reorganize if need be [14]. As expected, aging promulgates limit resources and energy deficiency to sustain such developmental processes, thus cellular senescence is a common event [15]. Consequently, there is a variety in the patterns of myelination, with qualitative- and quantitative-ontogenic checkpoints, throughout human life.
In this review, we focus on the de novo synthesis of myelin referred to herein as myelinogenesis. This is the primordial pattern of myelination, which starts prenatally and predominates during the first two years of human life [16]. In order for myelinogenesis to happen, neural stem cells (NSCs) need to undergo specific developmental stages, with the process of oligodendrogenesis, as well as additional steps for the maintenance of these primary myelin sheaths. Interestingly, it is possible that lifelong myelinogenesis may still occur in specific CNS regions through quiescent, adult OPCs (aOPCs), based on miscellaneous factors, such as unmyelinated space, new OLs turnover, energy balance, and neural circuit activity [17]. Such processes are broadly defined as adaptive myelination or myelin remodelling/plasticity which is under fine regulation and is generally restricted. Lastly, another crucial factor that may trigger myelinogenesis is injury and disease, such as demyelination, and is discussed briefly towards the end, with a process known as remyelination.

2. Myelinogenesis and Myelin Development: A Spatiotemporal Coordination

2.1. Primordium Regions of OPCs

The mammalian CNS emerges from an ectodermal, neuroepithelial lining of the neural tube in the developing embryo [9,18]. Multiple divisions give rise to radial glia (RG), a multipotent neural stem population that colonizes the newly-formed ventricular walls (Figure 1) [18,19]. The VZ is the primary embryonic site for OPCs production through asymmetrical division of the RG cells. In mice, OPCs are firstly detected in the ventral VZ closer to the floor plate on embryonic day 12.5 (E12.5), and in humans at gestational week (GW) 6.5 (~E45) [20]. More specifically, the outer SVZ (oSVZ) is an enlarged cortical germinal zone only generated in humans [21]. In oSVZ, a distinct RG cell population termed as outer RG (oRG) is located peripherally and gives rise to a transit-amplifying population, which is an additional source of OPCs supplying the human cortex [19,21].
In the human forebrain, the first wave of OPCs originates from the medial ganglionic eminence (MGE) and the anterior entopeduncular area (AEP), while a second batch emerges postnatally from the lateral or caudal ganglionic eminences, establishing a sufficient amount of OPCs in the cerebral cortex [22]. OPCs of the human forebrain appear in the SVZ of the MGE at GW7.5, whilst at E12 in mice [19]. In the spinal cord, the majority of the nascent OPCs (about 80% of the total number) complete their formation at the motor neuron progenitor (pMN) domain of the ventral spinal cord, while the pool is enriched later at E15.5 by additional OPCs migrating from dorsal regions [23]. Lastly, the cerebellar OPCs are derived from the metencephalic ventral rhombomere 1 region, manifesting their presence at E16.5 and are reinforced additionally with a secondary population originating from the cerebellar VZ [10].

2.2. Molecular Signals Driving Myelinogenesis

As has been articulated from the experimental evidence, the inauguration of myelinogenesis necessitates the formation of OPCs from multipotent NSCs, which ultimately give rise to mature myelinating OLs through a multistep process (Figure 1) [18,24]. A vital step herein lies in OPCs’ ability to migrate toward miscellaneous sites and proliferate, based predominately on environmental stimuli. These cells become post-mitotic, exiting the cell cycle to express a substantial amount of myelin-associated proteins and differentiate into mature pre-myelinating OLs [23]. Following the proper recognition, targeting and ensheathing specific nerve fibers is the subsequent critical milestone where each pioneer process creates lamellar extensions that stretch and elaborate circumferentially around the target axon [24]. As a new membrane is generated at the leading edge of the forming myelin sheath’s inner tongue, which starts to resemble a spiral cross-sectional shape, the sheath continues to spread along the axonal length. The secured stability and maintenance of a newly-formed myelin sheath is the concluding event. Specific developmental cues and molecular drivers regulate all the aforementioned cellular activities and are enlisted in full capacity in Table A1, Table A2 and Table A3.

2.2.1. Formation of OPCs

OPCs being generated from the ventral VZ are under the influence of the morphogen molecule Sonic hedgehog (SHH) secreted from the notochord, while the dorsal counterparts are SHH-independent [25,26]. SHH signalling drives NSCs into a neuronal or OLs lineage fate superseding the effect of bone morphogenetic proteins (BMPs) which favour astroglial generation (Figure 1) [27,28]. Early secretion of SHH promotes motor neuron lineage formation, while interaction in later time periods promotes OLs differentiation [29]. Interestingly, the concentration of SHH can be controlled by sulfatase 1 expression in the ventral neuroepithelium prior to OPCs specification [30], whereas fibroblast growth factor (FGF) signalling is of paramount importance for further OLs differentiation, especially in the spinal cord [31,32].
Oligodendrocyte transcription factor 2 (OLIG2) is the primary regulator of OPCs generation [33,34], and its gene expression can be potentially repressed throughout the pre to postnatal period by paired box 6 (PAX6), Brahma-related gene-1 (BRG1), Iroquois homeobox 3 (IRX3), histone deacetylase (HDAC) 1, HDAC2, Distal-less homeobox (DLX) 1 and DLX 2 [35,36,37,38,39,40,41]. On the other hand, oligodendrocyte transcription factor 1 (OLIG1) is activated in later stages of OLs development [42]. Interestingly, the Hes family bHLH transcription factor (HES1) can drive RG to an astrocytic phenotype [43], while co-occurrence of OLIG2 with neurogenin-1 or neurogenin-2 supports motor neuron production [38,44,45].
Members of the sex-determining region Y-box transcription factor (SOX) family, such as SOX1, SOX2, and SOX3, can also direct OPCs towards a neuronal fate [33], in contrast to SOX8, SOX9, and SOX10, which favour the turnover of NSCs to OPCs in an autonomous manner [34,35,36]. Additionally, transcription factor forkhead box J1 (FOXJ1) supports the retention of RGs as ependymal cells throughout ventricles. Lastly, glioma-associated oncogene family zinc finger 2 (GLI2), myelin transcription factor 1 (MYT1), NK2 homeobox 6 (NKX2-6), and chromodomain-helicase-DNA-binding protein 8 (CHD8), among others (Table A1), are embryonic cues for OLs specification that vary within CNS regions indicating brain region specificity [37,38,39,40].

2.2.2. Migration

SHH presence is equally catalytic to OPCs migration [41]. Platelet-derived growth factor subunit A (PDGFA) and its cognate receptor, PDGF receptor alpha (PDGFRα), are essential positive drivers for OPCs migration [42]. In line with this, SOX5, SOX6, SOX9, and SOX10 stimulate the migration, ensuring PDGF responsiveness [43,44]. Chondroitin sulfate proteoglycan neuron-glia antigen 2 (NG2) and ephrin-B2/B3 molecules control OPCs polarity and contact abilities, promoting or intercepting migration, respectively [45,46]. Nestin, neural cell adhesion molecule (NCAM), and OLIG1 can also act as chemoattractants, determining cytoskeletal plasticity as well as OPCs motility [47,48,49,50,51]. Other migration chemoattractants are 2′,3′-cyclic nucleotide 3′ phosphodiesterase (CNPase), OLIG2, hepatocyte growth factor (HGF), thrombospondin 1, endothelin 1 (ET-1), oligodendrocyte specific protein (OSP), OSP–associated protein (OAP-1), N-cadherin (NCAD), merosin, fibronectin, and integrin subunit beta 1 (αvβ1 integrin) [52,53,54,55,56,57,58,59,60]. Spassky et al. suggested that netrin-1 is a candidate mediator for chemoattraction during migration [61]. However, other studies considered this molecule as a chemorepellent, antagonizing PDGF [62,63].
More growth factors and associated molecules, such as vascular endothelial growth factor A (VEGF-A) combined with VEFG receptor 2 (VEGFR2), can act as chemoattractant molecules for OPCs migration along with miscellaneous members of the transforming growth factor beta (TGF-β) family (e.g., BMP7 and BMP4), and Gαi-linked sphingosine-1-phosphate receptor (S1PR) 1 and S1PR3 [64,65,66]. In contrast to these specific sphingosine molecules, S1PR2 and S1PR5 negatively regulated migration [66]. Moreover, although C-X-C motif chemokine receptor (CXCR) 4, C-X-C motif chemokine ligand (CXCL) 12 and semaphorin 3F have chemoattractive effects on the OPCs migration, semaphorin 3A, CXCL1, and CXCR2 inhibit migration [61,67,68]. In addition, tenascin-c inhibited OPCs migration, whilst both claudin (CLDN) 1 and CLDN3 supported OPCs relocation, validated also in human specimens [59,69,70].

2.2.3. Proliferation

Specific driver molecules that participate in migration, such as PDGFA and PDGFRα, contribute additionally to the OPC proliferation [47,71]. Interestingly, in the spinal cord, the mitogenic effect of PDGF was enhanced by chemokine CXCL1 and CXCR2 [44,72], while CXCL12 had a proliferative effect on OPCs, mediated by its receptor CXCR4 [73]. More growth factors, such as FGF2, brain-derived neurotrophic factor (BDNF), and epidermal growth factor (EGF) are shown to play a vital role in OPCs proliferation [74,75,76].
Associate developmental pathways are also implicated in this step; PDGF-mediated proliferation depends largely on Wnt/β-catenin and PI3K/AKT/mTOR pathways [77,78]. Furthermore, jagged canonical Notch ligand 1 (JAG1) promotes OPCs proliferation and critically blocks the subsequent differentiation step [79]. Carrying on subcellular, CHD7 and CHD8 regulate gene expression in specific brain regions [80,81]. Another member of the SOX family, SOX9, supports the development of OLs in the cerebellum, regulating the timing of proliferation [82]. MYT1, NCAM, cyclin-dependent kinase inhibitor 1B (p27KIP1), oligodendrocyte myelin glycoprotein (OMgp), and tubulin polymerization promoting protein (TPPP) are negative regulator cues for OPCs proliferation [83,84,85,86,87]. Interestingly, overexpression of inhibitor of DNA binding (ID) 2 and ID4 enhances proliferation [88,89]. Similarly, expression of SHH, HGF, neurotrophin-4 (NT-4), noggin, superoxide dismutase 1 (SOD1), neurotrophin-3 (NT-3), achaete-scute family bHLH transcription factor 1 (ASCL1), PAX6, CLDN1, and CLDN3 promotes the proliferation process [41,54,70,90,91,92,93,94,95].
Integrin-mediated signalling and, more specifically, OSP, OAP-1, αvβ1 integrin, αvβ3 integrin, fibronectin and laminin are pivotal mediators in cytoskeletal remodelling of proliferating OPCs [56,96,97]. Gadea et al. revealed that ET-1 is a candidate molecule for enhancing cell migration without influencing proliferation [60]. Later, Adams and colleagues underscored that loss of ET-1 reduces OPCs proliferation in the developing SVZ via directly binding to endothelin type B receptor (ETBR) [98]. A reduced OPCs proliferation is observed in GS homeobox 1/2 (Gsx1/2) mutant embryos, whereas galectin-4 (GAL-4) treatment increased the proliferation [99,100]. At last, NRG1 and SOX2 induce cell division [101,102]; however, the latest data demonstrate that NRG1 acting via ErbB did not alter the proliferation state of OPCs [103].

2.2.4. Differentiation

OLIG1 and OLIG2 are heavily involved in the post-proliferating step of myelinogenesis, defining the initiation of OPCs differentiation (Figure 1) [51,53,104], while BMPs seem to inhibit this process by downregulating myelin protein expression [105]. The effect can be reversed by using a physiological antagonist of BMP4, such as noggin, which may restore differentiation [91,106,107]. OLIG2 appears to interact with a variety of factors, such as ASCL1, BRG1, transcription factor 4 (TCF4), and SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) to ensure proper OPCs differentiation [108,109,110,111,112]. G protein-coupled receptor 17 (GPR17) can act as a downregulator of OLIG1 that negatively controls the maturation and coordinates the generation of myelinating OLs from pre-myelinating OLs through ID proteins [113]. Although overexpression of ID2 and ID4 both regulate myelin gene expression by inhibiting OLs differentiation [89,114], they are not the major in vivo repressors of differentiation [115]. Moreover, decreased levels of OLIG1 and myelin regulatory factor (MYRF) were observed under early growth response 1 (EGR1) and SOX11 overexpression, delineating the inhibitory action of the latest in OPCs differentiation [116,117]. Intriguingly, MYRF is a unique regulator participating in the late stages of OLs maturation and myelination, while the action of the other OLs’ lineage transcription factors is restricted on OPCs specification or initial differentiation of OLs [118].
SOX family proteins are also participating in the OLs differentiation. In particular, SOX2 and SOX3, through negative regulation of miR145, promote OLs maturation [119], while SOX5 and SOX6 increase PDGFRα expression, maintaining OLs in their immature state [44]. For the terminal differentiation of OLs, SOX8, SOX9, and SOX10 are required [82,120,121,122]. The state of myelinogenesis-associated gene expression is uniformly affected by NKX2-2 and NKX2-6 [40,123,124]. Ji et al. suggested a mechanism regarding NKX2-2-mediated inhibition of OLs differentiation via regulation of sirtuin 2 (SIRT2), which generally is a positive cue for OLs maturation [125]. Similarly, sirtuin 1 (SIRT1) participates in the differentiation of OPCs during development [126] through cytoskeleton-related OLs proteins. The Kruppel-like factor 6 (KLF6) is another transcription factor promoting OPCs differentiation through glycoprotein 130 (GP130)-signal transducer and transcription activator 3 (STAT3) signalling [127]. Growth factor-wise, BDNF is a regulator of OLs differentiation operating via binding to tyrosine receptor kinase B (TrkB) and enhancing the MAPK pathway to upregulate gene expression during OLs maturation [75,77,128]. Evidently, NT-3 is important for the transition of immature OLs to myelin-forming cells by recruiting c-Fos protein-activating protein kinase C (PKC) and tyrosine kinase activities [129,130]. Insulin-like growth factor 1 (IGF-1) is another main factor in assisting the development of OPCs to mature OLs [131]. In accordance with that, GRB2 associated binding protein 1 (GAB1) absence decreased OLs differentiation, acting as a novel target of PDGF [132]. Incidentally, Canoll et al. suggested that NRG1 is a negative regulator of OPCs differentiation [101], while Brinkmann et al. later demonstrated that NRG1 is required for OPCs differentiation [103].
As far as metabolism is concerned, quaking homolog, KH domain RNA binding (QKI)-5 forms a complex with sterol regulatory element-binding transcription factor 2 (SREBF2) that regulates the transcription of genes responsible for cholesterol biosynthesis in OLs during differentiation [133]. Lack of transactive response DNA-binding protein 43 (TDP-43) results in lower SREBF2 and low-density lipoprotein receptor (LDLR) expression and cholesterol levels in vitro and in vivo, indicating the potential role of TDP-43 in cholesterol homeostasis in OLs, which is linked with the proper completion of OLs development [134]. In the same manner, ectonucleotide pyrophosphatase/phosphodiesterase 6 (ENPP6) participates in OLs maturation via a supplement of OLs with choline [135]. Most importantly, triiodothyronine (T3) is a key molecule for blocking OPCs proliferation and promoting their differentiation into mature OLs [136,137]. Thyroid hormone receptor alpha (TRα) is found both in OPCs and mature OLs, whilst thyroid hormone receptor isoform beta 1 (TRβ1) is located only in mature OLs [138]. The OPCs differentiation is mediated by the TRα, while TRβ1 is responsible for promoting myelinogenesis in later stages [77]. Overexpression of HES5 decreases the levels of TRβ1 receptors, while ASCL1 increases them, demonstrating their role in regulating OLs differentiation timing [139]. The neurogenic locus notch homolog protein 1 (NOTCH1) is another receptor that also regulates the differentiation timing [140]. Interestingly, JAG1 is a receptor’s ligand responsible for inhibiting OLs differentiation, while contactin 1 (CNTN1) is another ligand with the opposite function [79,141].
Other membrane molecules which repress OPCs differentiation are NCAM and leucine-rich repeat, and Ig-like domain-containing Nogo receptor interacting protein 1 (LINGO-1) [142,143]. OLs maturation is negatively affected by GAL-4 and galactosylceramidase (GALC), while prominin-1, GLI2, p21-activated kinase 1 (PAK1), myelin-associated glycoprotein (MAG), SOD1, ciliary neurotrophic factor (CNTF), and inward rectifying potassium channel 4.1 (Kir4.1) are crucial for proper differentiation [38,95,100,144,145,146,147,148,149]. On the other hand, proper completion of OLs differentiation requires zinc finger protein 191 (ZFP191) [150]. Microtubule-associated protein 2 (MAP2), microtubule-associated protein tau (MAPT), CNPase, and TPPP may be involved in OLs differentiation by organising the microtubule system, similar to fasciculation and elongation protein zeta 1 (FEZ1), which is responsible for developing OLs processes’ arbour [87,151,152,153]. Additionally, important molecules being involved in the completion of OLs development are OMgp, brain enriched myelin-associated protein 1 (BCAS1) and glutathione (GSH) [154,155,156,157]. Myelin proteolipid protein (PLP) and myelin basic protein (MBP) are the main myelin structural proteins, but it is suggested that they play an additional role in OLs differentiation [158,159]. CLDN1 and CLDN3 control MBP, OLIG2, PLP, and SOX10 expression: these molecules are essential for OLs differentiation, indicating that claudins are needed [70]. Finally, connexin 47 (CX47) and adenosine triphosphate binding cassette subfamily D member 1 (ABCD1) may support OLs during their differentiation, aiding in gap junction coupling and reducing oxidative stress, respectively [160,161,162,163,164].

2.2.5. Ensheathment

Multiple positive cues are important for the inauguration of ensheathment (Figure 2). Amongst the prime ones with a positive effect on axon-glial junction maintenance is NCAD, which regulates the interaction between OLs processes and axons [165]. The L1 cell adhesion molecule (L1-CAM) and laminin expressed in axons bind to contactin and integrin located in OLs [166]. Upon the formation of the first loops/wraps, neurofascin 155 (NF155), located in paranodal loops, forms a well-defined complex with contactin-associated protein (CASPR) and CNTN1, transmembrane proteins which are expressed in axons [167,168,169]. The activation of this complex has a pivotal role in myelin targeting, sheath growth, organisation of paranodal loops and, therefore, supporting the axoglial junction [170,171]. However, CASPR does not participate in myelin targeting [170]. In juxtaparanodes, the axoglial junction is strengthened when transient axonal glycoprotein-1 (TAG-1), a crucial molecule for maintaining enrichment of Kv1.1/Kv1.2 channels [172], interacts with CASPR2. Regarding internodal axoglial adhesion, glial cell adhesion molecule (CADM) 4 binds to axonal CADM2 and CADM3, facilitating myelin targeting, axon wrapping, and myelin sheath growth [173]. Similarly, CADM1b strongly binds to axonal CADM2, positively regulating ensheathment and strengthening the junction [174]. In the same region of the myelin sheath, MAG binds to ganglioside in axons, especially ganglioside GD1a and GT1b, and enforces the junction’s stability [175,176].
Based on several studies, ephrins (A, B) and cognate receptors (A, B) have dual roles that rely on location and expression. While ephrin receptor (Eph) A4 in OLs is activated by axonal ephrin-A1 ligand, which inhibits the stability of axoglial junctions needed for ensheathment, EphA4, expressed in the axon surface, interacts with ephrin-B, promoting myelin sheet formation [177,178]. In addition, EphB1 of axons is activated through ephrin-B in OLs, which in turn stimulates myelinogenesis [178]. The axonal ephrinB2 via binding with EphB OLs receptor influences integrin activation, reducing myelin sheet formation [178]. The list of negative cues includes LINGO-1, which is located in both axons and OLs, and self-interacts in trans to control the number of targeted axons inhibiting myelinogenesis [143,179]. The NCAM is a cell adhesion molecule negatively regulating myelinogenesis. The downregulation of this protein is essential for promoting myelin formation during development, as myelinogenesis occurs only on NCAM negative axons [180]. A somatodendritic protein, junctional adhesion molecule 2 (JAM2) inhibits oligodendroglial interaction, suppressing myelinogenesis [181]. Apart from the somatodendritic molecules, GAL-4 is expressed only to unmyelinated segments of neurons in hippocampal and cortical regions; this protein is demonstrated as the first identified inhibitor of myelinogenesis in axons [182]. Of particular interest is the possible role of OLIG1 in axonal recognition during myelinogenesis (Table A2) [183].

2.2.6. Myelin Sheath Growth and Preservation

The long-term membrane expansion and maintenance of the newly-formed myelin sheath is the final step in completing myelinogenesis and is utterly controlled by the major myelin proteins (Table A3). The most abundant myelin proteins are PLP (>50%) and MBP (~15%), having a significant role in the stabilization of the myelin structure [24,52,184]. The disruption of PLP gene expression presents impaired membrane compaction [185]. MAG, on the other side, is the third most abundant protein in CNS myelin (~5%), and does not seem to contribute to maintenance as much as it does to the previously described initial interaction between OLs and axons [147,186]. Interestingly, myelin oligodendrocyte glycoprotein (MOG) [187,188], CNPase [52,189], myelin-associated oligodendrocyte basic protein (MOBP) [190], and OMgp [86,191,192], all minor CNS myelin proteins (<1%), need more investigation on how they influence the formation and maintenance of myelin sheaths in compact myelin.
OLs microtubule stability is mediated by MAP2 and MAPT [151], while CX32 and CX47 participate in maintenance [161]. Claudins, such as OSP, CLDN1, and CLDN3, play a pivotal role as well [70,185]. Transcription factors that participate in the lamellar extension process are SOX8, SOX10, NKX2-2, NKX6-2, and MYRF [35,122,193,194]. Transmembrane protein (TMEM) 98, which inhibits the self-cleavage of MYRF, ID4, and OLIG1, could also be involved in the process [114,195], whereas OLIG2 is expressed only until myelin membranes’ production is completed [183,196]. In addition, the ERK1/2 MAP kinase pathway is indispensable in maintaining myelinated axons via FGF–FGF receptor 1 and 2 (FGFR1 and FGFR2) [197,198]. Experiments in Hdac3-mutant optic nerves raised the possibility that HDAC3 is also necessary for myelin integrity [199].
Proper cholesterol biosynthesis is prioritized in myelinogenesis, with QKI regulating this cholesterol production via SREBF2. Specifically, QKI-5 acts synergistically with peroxisome proliferator-activated receptor beta (PPARβ)-retinoid X receptor alpha (RXRα) activating transcription of the response in fatty acid metabolism genes. This operation of QKI-5 is significant for maintaining myelin homeostasis [133]. The ceramide galactosyl transferase (CGT) is a key enzyme for catalyzing GALC synthesis, while ceramide sulfotransferase (CST) is responsible for converting GALC to sulfatide [200,201]. Both CST and CGT mutant animals showed a regionally specific loss of myelin stability [200]. Thus, GALC and sulfatide have a pivotal role in the long-term maintenance of myelin, with the GALC being more crucial for myelin development than its assembly [200,201]. Additionally, peroxisomal metabolism also influences myelin survival [202]. For example, a peroxisomal transmembrane protein responsible for very long-chain fatty metabolism is encoded by the ABCD1 gene and is key in maintaining myelin stability [164,203]. Lastly, the age-dependent changes of TMEM10 might be linked with its action in maintaining CNS myelin [204].

2.3. Myelin Formation after Infancy

Although myelinogenesis has been described in the nascent developmental years, myelination does naturally occur for the duration of a person’s life to promote learning and memory through brain circuit plasticity [205], or as remyelination after an injury [206]. The synaptic plasticity has been studied in depth; however, a newly discovered form of brain plasticity, namely myelin plasticity or myelin remodelling, is under intensive investigation [205]. Extrinsic factors can influence, either positively or negatively, this remodelling in the toddler, adolescent, and adult brain. For example, since myelin formation is sensitive to experience, sensory stimulation may upregulate myelination, while sensory or social deprivation can potentially downregulate axon ensheathment [205,207]. Myelin remodelling initiates when pre-existing OPCs recruit or directly differentiate into newly-formed mature OLs, whereas existing OLs have the ability to engage in plasticity [205]. The principal cues for this “adaptive” myelination should not be different from the ones we scrutinize in this review.
The regenerative process following injury also presents many similarities with specific steps of myelinogenesis [208]. The neonatal OPCs are maintained in a resting, quiescent state through adulthood, and they are referred to as adult aOPCs, constituting ~6% of all cells in the CNS [206]. Interestingly, aOPCs have a transcriptome similar to mature OLs. After injury, the innate immune response activates aOPCs, transforming them into a neonatal-like transcriptome [209]. The activation of aOPCs is followed by their proliferation, migration, and final differentiation into mature OLs. Older literature describes these aOPCs as the primary remyelinating cells [210]. Nevertheless, newer research has suggested that neural progenitors in SVZ, Schwann cells, and surviving mature OLs are also implicated in the remyelinating process [211,212,213].
The myelination efficiency is age-dependent, as the impairment of aged OPCs to recruit and differentiate into mature OLs leads to decreased remodelling and remyelination [214]. The nutrient support of OLs is highly compromised in aging due to the presence of senescent astrocytes, leading to decreased cholesterol biosynthesis which in turn weighs in the impaired OLs membrane development [15,215,216]. This age-related energy depletion that decreases the myelination efficiency is further fed from the accumulation of DNA damage while rendering the neurons vulnerable to oxidative stress through free radicals [15,217]. Additionally, the ineffectiveness of microglia, which translates to aged phagocytes to clear out impaired myelin, is a potential aetiology for the downregulation of remyelination [218]. Taken all together, the detailed investigation of cues that drives de novo myelination could be a crucial point for revisiting them in demyelination and remyelination of the adult CNS, a concept that is discussed briefly in the following section.

3. Myelinogenesis in Disease and Beyond

Although aging is a natural process that leads to a decreased turnover of functional OLs and diminished myelin formation, the integrity of myelinogenesis can be highly compromised in pathological situations such as demyelination, characterized by extensive myelin loss [219]. This condition has to be distinguished from dysmyelination, which is a genetic-based anomaly affecting basic myelin proteins and leads to uneven/not properly compacted myelin sheaths [219]. Demyelinating diseases could be divided into many categories; according to their pathogenesis mechanism, which mostly implicate environmental factors, nutritional deficits, presence of myelinotoxic agents, or virus-mediated impairments. In quite frequent cases, immune system mediators are deregulated, leading to autoimmune inflammatory demyelination [219,220]. Among the three most prevalent inflammatory demyelinating diseases are multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and acute disseminated encephalomyelitis (ADEM).
In this review, we summarized all the potential molecules responsible for the long-term maintenance of myelin along the axoglial junction (see Section 2.2.5 and Section 2.2.6), serving simultaneously as key factors in demyelinating disease sequelae. Recent data revealed that impaired mitochondrial function and oxidative stress are also candidate pathophysiology mechanisms for demyelinating diseases [221]. Berghoff et al. demonstrated that disruption of cholesterol metabolism alters brain lipid metabolism in CNS and is associated with neurological diseases such as autoimmune inflammatory conditions, including MS [222]. Nonetheless, under such circumstances, an autoimmune attack generates myelin debris from damaged myelin [223]. These components impair the CNS remyelination by obstructing OPCs and OLs functionality while triggering additional deleterious immune responses, also known as epitope spreading [213,223,224]. The clearance of myelin debris is crucial for rearrangement since recent studies suggest that the failure of myelin clearance leads to inefficient remyelination [225,226].
Remyelination can be spontaneous or in an experimental setup, achieved by the providence of an exogenous source of neural precursor cells (NPCs) with myelinating potential [227,228]. In various transplantation paradigms, it is shown that these cells can either exert an in situ myelinating effect, as seen and applied successfully in spinal cord injury (SCI) cases [229,230], or by instructing and enhancing the capacity of endogenous cells to remyelinate, documented in experimental autoimmune encephalomyelitis (EAE) [208,231,232] (324). Proposed mechanisms of action also underline immunomodulatory effects rather than direct cell replacement [233,234]. Nevertheless, the scarce population of surviving mature OLs after demyelination is shown to be less effective in comparison to newly created ones [213,235,236,237]. Towards this trajectory, which is a fully functional recruitment of aOPCs to form myelinating OLs [208,238] (324, 325), it is extremely important to comprehend the developmental molecular cues and factors governing the process of myelinogenesis (see Section 2.2.1, Section 2.2.2, Section 2.2.3, Section 2.2.4), since these same molecules can be candidate targets for therapeutic intervention in demyelinating diseases.

4. Conclusions

Through this comprehensive review, we attempt to list and categorize the genes and proteins that act as developmental morphogens to the CNS development and, more specifically, those that are activated in the process of oligodendrogenesis. The fully functional OLs, originating from unspecialized stem cells, are able to identify newly-formed axons which emanate and branch in regions that need fast conduction early in life, completing their task of myelinogenesis. Some of these cells persist in adult life in an intermediate, dormant phenotype scattered or organized around the primordial niches. An argument that was intended to bring into attention is how the powerful dynamics that shape myelination, which is naturally declining as we age, can be sustained, or even re-engaged after an injury or demyelinating disease. In the current era, transcriptomic profiling or metabolomic data can potentially give an answer as to which of the enlisted molecules, drivers, and regulators should be prioritized.

Author Contributions

I.D. and P.T., writing—original draft preparation and visualization; M.E.M., S.M. and D.M., conceptualization, review and editing; E.K., M.B., S.P. and N.G., review and editing. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


OPCsOligodendrocyte precursor cells
CNSCentral nervous system
NSCsNeural stem cells
aOPCsAdult oligodendrocyte precursor cells
EEmbryonic day
GWGestational week
VZVentricular zone
SVZSubventricular zone
RGRadial glia
oSVZOuter subventricular zone
MGEMedial ganglionic eminence
MSMultiple sclerosis
ABCD1Adenosine triphosphate binding cassette subfamily D member 1
ASCL1Achaete-scute family basic helix-loop-helix transcription factor 1
BDNFBrain-derived neurotrophic factor
BMP4Bone morphogenetic protein 4
BMP7Bone morphogenetic protein 7
CADM1bCell adhesion molecule 1b
CADM2Cell adhesion molecule 2
CADM3Cell adhesion molecule 3
CADM4Cell adhesion molecule 4
CASPRContactin-associated protein
CASPR2Contactin-associated protein-like 2
CGTCeramide galactosyl transferase
CHD7Chromodomain-helicase-DNA-binding protein 7
CHD8Chromodomain-helicase-DNA-binding protein 8
CLDN1Claudin 1
OSPOligodendrocyte specific protein
CLDN3Claudin 3
CNPase2′,3′-cyclic nucleotide 3′ phosphodiesterase
CNTN1Contactin 1
CSTCeramide sulfotransferase
CX32Connexin 32
CX47Connexin 47
CXCL1C-X-C motif chemokine ligand 1
CXCL12C-X-C motif chemokine ligand 12
CXCR2C-X-C motif chemokine receptor 2
CXCR4C-X-C motif chemokine receptor 4
DLX1Distal-less homeobox 1
DLX2Distal-less homeobox 2
EphA4Ephrin receptor A4
EphB1Ephrin receptor B1
EphB2Ephrin receptor B2
ET-1Endothelin 1
FGF2Fibroblast growth factor 2
FGFR1Fibroblast growth factor receptor 1
FGFR2Fibroblast growth factor receptor 2
GLI2Glioma-associated oncogene family zinc finger 2
HDAC1Histone deacetylase 1
HDAC2Histone deacetylase 2
HDAC3Histone deacetylase 3
HES5Hairy and enhancer of split family basic helix-loop-helix transcription factor 5
HGFHepatocyte growth factor
ID2Inhibitor of DNA binding 2
ID4Inhibitor of DNA binding 4
JAG1Jagged canonical Notch ligand 1
LINGO-1Leucine-rich repeat and Ig-like domain-containing Nogo receptor interacting protein 1
MAGMyelin-associated glycoprotein
MAP2Microtubule-associated protein 2
MAPTMicrotubule-associated protein tau
MBPMyelin basic protein
MYRFMyelin regulatory factor
MYT1Myelin transcription factor 1
NCAMNeural cell adhesion molecule
NKX2-2NK2 homeobox 2
NKX2-6NK2 homeobox 6
NKX6-2NK6 homeobox 2
NRG1Neuregulin 1
NT-3Neurotrophin 3
OAP-1Oligodendrocyte specific protein–associated protein
OLIG1Oligodendrocyte transcription factor 1
OLIG2Oligodendrocyte transcription factor 2
OMgpOligodendrocyte myelin glycoprotein
PAX6Paired box 6
PDGFAPlatelet-derived growth factor subunit A
PDGFRαPlatelet-derived growth factor receptor alpha
PLPMyelin proteolipid protein
QKIQuaking homolog, KH domain RNA binding
S1PR1Sphingosine-1-phosphate receptor 1
S1PR2Sphingosine-1-phosphate receptor 2
S1PR3Sphingosine-1-phosphate receptor 3
S1PR5Sphingosine-1-phosphate receptor 5
SHHSonic hedgehog signaling molecule
BRG1Brahma-Related Gene-1
SOD1Superoxide dismutase 1
SOX1Sex-determining region Y-box transcription factor 1
SOX10Sex-determining region Y-box transcription factor 10
SOX11Sex-determining region Y-box transcription factor 11
SOX2Sex-determining region Y-box transcription factor 2
SOX3Sex-determining region Y-box transcription factor 3
SOX5Sex-determining region Y-box transcription factor 5
SOX6Sex-determining region Y-box transcription factor 6
SOX8Sex-determining region Y-box transcription factor 8
SOX9Sex-determining region Y-box transcription factor 9
SREBF2Sterol regulatory element-binding transcription factor 2
TRαThyroid hormone receptor alpha
TRβ1Thyroid hormone receptor isoform beta 1
TDP-43Transactive response DNA-binding protein 43
TMEM10Transmembrane Protein 10
TMEM98Transmembrane protein 98
TPPPTubulin polymerization promoting protein
VEGF-AVascular endothelial growth factor A
VEGFR2Vascular endothelial growth factor receptor 2
αvβ1 integrinIntegrin subunit beta 1
αvβ3 integrinIntegrin subunit beta 3

Appendix A

The following appendix contains all the genes and relevant chromosomal loci from proteins involved in myelinogenesis in relation to their biological role. This data is supplemental to the main text based on the current knowledge and literature on cues driving oligodendrocyte development, ensheathment and myelin maintenance.
Table A1. Molecular drivers and morphogens in specification, migration, proliferation, and differentiation of OPCs.
Table A1. Molecular drivers and morphogens in specification, migration, proliferation, and differentiation of OPCs.
Gene *Chromosomal Locus *Protein *Biological RoleReference
ABCD1Xq28ATP binding cassette subfamily D member 1Differentiation[163,164]
ADGRG116q21Adhesion G protein-coupled receptor G1Proliferation[239]
ANOS1Xp22.31Anosmin 1Migration[240]
ASCL112q23.2Achaete-scute family bHLH transcription factor 1Specification; Proliferation; Differentiation[93,108,139,241]
BCAS120q13.2Brain enriched myelin-associated protein 1Differentiation[156,157,242]
BDNF11p14.1Brain-derived neurotrophic factorProliferation; Differentiation[75,128]
BMP220p12.3Bone morphogenetic protein 2Specification; Differentiation[27,105]
BMP414q22.2Bone morphogenetic protein 4Specification; Migration; Differentiation[28,65,105]
BMP720q13.31Bone morphogenetic protein 7Migration[65]
CDH218q12.1Cadherin 2Migration[57]
CDKN1B12p13.1Cyclin-dependent kinase inhibitor 1BProliferation[85]
CHD78q12.2Chromodomain-helicase-DNA-binding protein 7Proliferation; Differentiation[80,243]
CHD814q11.2Chromodomain-helicase-DNA-binding protein 8Specification; Proliferation; Differentiation[80,81]
CLDN13q28Claudin 1Migration; Proliferation; Differentiation[70]
CLDN37q11.23Claudin 3Migration; Proliferation; Differentiation[70]
CLDN113q26.2Claudin 11Migration; Proliferation[56]
CNP17q21.22′,3′-cyclic nucleotide 3′ phosphodiesteraseMigration; Differentiation[52,153]
CNTF11q12.1Ciliary neurotrophic factorProliferation; Differentiation[148,244]
CNTFR9p13.3Ciliary neurotrophic factor receptorProliferation[244]
CNTN112q12Contactin 1Differentiation[141]
CREB3L27q33CAMP responsive element binding protein 3 like 2Differentiation[243]
CSPG415q24.2Chondroitin sulfate proteoglycan 4Proliferation[245]
CXCL14q13.3C-X-C motif chemokine ligand 1Migration; Proliferation[67,72]
CXCL1210q11.21C-X-C motif chemokine ligand 12Migration; Proliferation[68,73]
CXCR22q35C-X-C motif chemokine receptor 2Migration; Proliferation[67,72]
CXCR42q22.1C-X-C motif chemokine receptor 4Migration; Proliferation[68,73]
DLX12q31.1Distal-less homeobox 1Specification[246]
DLX22q31.1Distal-less homeobox 2Specification[246]
DUSP1520q11.21Dual specificity phosphatase 15Differentiation[247]
EDN16p24.1Endothelin 1Migration; Proliferation[60,98]
EDNRB13q22.3Endothelin receptor type BProliferation[98]
EFNB213q33.3Ephrin B2Migration; Proliferation[46,248]
EFNB317p13.1Ephrin B3Migration[46]
EGF4q25Epidermal growth factorProliferation[76]
EGR15q31.2Early growth response 1Differentiation[116]
ENPP64q35.1Ectonucleotide pyrophosphatase/phosphodiesterase 6Differentiation[135]
EPHB21p36.12Ephrin receptor B2Migration; Proliferation[46,248]
FEZ111q24.2Fasciculation and elongation protein zeta 1Differentiation[152]
FGF24q28.1Fibroblast growth factor 2Specification; Migration; Proliferation[240,249]
FGFR18p11.23Fibroblast growth factor receptor 1Migration; Proliferation[240,249]
FGFR210q26.13Fibroblast growth factor receptor 2Specification[31,249]
FGFR34p16.3Fibroblast growth factor receptor 3Proliferation[249]
FLT113q12.3Fms related receptor tyrosine kinase 1Proliferation[250]
FN12q35Fibronectin 1Migration; Proliferation[59,96]
GAB14q31.21GRB2-associated binding protein 1Differentiation[132]
GDPD2Xq13.1Glycerophosphodiester phosphodiesterase domain containing 2Proliferation[244]
GJC21q42.13Gap junction protein gamma 2Differentiation[160,161,162,251]
GLI22q14.2GLI family zinc finger 2Specification; Differentiation[38]
GPR172q14.3G protein-coupled receptor 17Differentiation[113]
GPR377q31.33G protein-coupled receptor 37Differentiation[252]
GSX113q12.2GS homeobox 1Proliferation[99]
GSX24q12GS homeobox 2Specification; Proliferation[99,253]
HDAC11p35.2-p35.1Histone deacetylase 1Specification[254,255]
HDAC26q21Histone deacetylase 2Specification[254]
HES13q29Hes family bHLH transcription factor 1Specification[256]
HES51p36.32Hes family bHLH transcription factor 5Differentiation[139]
HEY18q21.13Hes related family bHLH transcription factor with YRPW motif 1Differentiation[257]
HGF7q21.11Hepatocyte growth factorMigration; Proliferation[54]
ID22p25.1Inhibitor of DNA binding 2Proliferation; Differentiation[89,113,115]
ID46p22.3Inhibitor of DNA binding 4, HLH proteinProliferation; Differentiation[88,113,114,115]
IGF112q23.2Insulin-like growth factor 1Proliferation; Differentiation[74,131]
IRX316q12.2Iroquois homeobox 3Specification[37]
ITGB110p11.22Integrin subunit beta 1Migration; Proliferation; Differentiation[56,58,258]
ITGB317q21.32Integrin subunit beta 3Proliferation[69,97]
JAG120p12.2Jagged canonical Notch ligand 1Proliferation; Differentiation[79]
JUN1p32.1Jun proto-oncogene, AP-1 transcription factor subunitProliferation[259,260]
KCNJ101q23.2Potassium inwardly rectifying channel subfamily J member 10Differentiation[149]
KDR4q12Kinase insert domain receptorMigration; Proliferation[64,250]
KLF610p15.2Kruppel-like factor 6Differentiation[127]
LAMA26q22.33Laminin subunit alpha 2Migration; Proliferation[96,261]
LAMA46q21Laminin subunit alpha 4Migration; Proliferation[96,261]
LAMA520q13.33Laminin subunit alpha 5Migration; Proliferation[96,261]
LGALS419q13.2Galectin-4Proliferation; Differentiation[100]
LINGO115q24.3Leucine rich repeat and Ig domain containing 1Differentiation[143]
MAG19q13.12Myelin-associated glycoproteinDifferentiation[147]
MAP22q34Microtubule-associated protein 2Differentiation[151]
MAPT17q21.31Microtubule-associated protein tauDifferentiation[151]
MBP18q23Myelin basic proteinDifferentiation[159]
MOBP3p22.1Myelin associated oligodendrocyte basic proteinDifferentiation[190]
MYRF11q12.2Myelin regulatory factorDifferentiation[117]
MYT120q13.33Myelin transcription factor 1Specification; Proliferation[39,83]
NCAM111q23.2Neural cell adhesion molecule 1Migration; Proliferation[47,48,84,142]
NES1q23.1NestinMigration; Proliferation[49,263]
NEUROG15q31.1Neurogenin 1Specification[37,264,265]
NEUROG24q25Neurogenin 2Specification[37,264,265]
NFIA1p31.3Nuclear factor I ASpecification[37,266]
NGF1p13.2Nerve growth factorProliferation[92,267]
NKX2-220p11.22NK2 homeobox 2Specification; Proliferation; Differentiation[37,108,123,124,268]
NKX2-68p21.2NK2 homeobox 6Specification; Differentiation[40]
NKX6-14q21.23NK6 homeobox 1Specification[26]
NKX6-210q26.3NK6 homeobox 2Specification[26]
NOG17q22NogginProliferation; Differentiation[91,106,107]
NOTCH19q34.3Notch receptor 1Proliferation; Differentiation[79,140]
NRG18p12Neuregulin 1Migration; Proliferation; Differentiation[101,103,269]
NTF312p13.31Neurotrophin 3Proliferation; Differentiation[92,129,130]
NTF419q13.33Neurotrophin 4Proliferation[90]
NTN117p13.1Netrin 1Migration[61,62,63]
NTRK29q21.33Neurotrophic receptor tyrosine kinase 2Proliferation; Differentiation[75,270]
OLIG121q22.11Oligodendrocyte transcription factor 1Migration; Differentiation[50,51,104,271]
OLIG221q22.11Oligodendrocyte transcription factor 2Specification; Migration; Differentiation[51,53,271]
OMG17q11.2Oligodendrocyte myelin glycoproteinProliferation; Differentiation[155]
OPALIN10q24.1Oligodendrocytic myelin paranodal and inner loop proteinDifferentiation[272,273]
PAK111q13.5-q14.1P21 (RAC1) activated kinase 1Differentiation[146]
PAX611p13Paired box 6Specification; Proliferation[94,274,275]
PDE54q26Phosphodiesterase 5ADifferentiation[276]
PDGFA7p22.3Platelet-derived growth factor subunit AMigration; Proliferation; Differentiation[42,277]
PDGFRA4q12Platelet-derived growth factor receptor alphaMigration; Proliferation; Differentiation[42,47,71,277]
PLP1Xq22.2Proteolipid protein 1Differentiation[158]
PRMT514q11.2Protein arginine methyltransferase 5Differentiation[278]
PROM14p15.32Prominin 1Differentiation[145]
QKI6q26QKI, KH domain containing RNA bindingDifferentiation[133,279]
RTN42p16.1Reticulon 4Migration[280]
S1PR11p21.2Sphingosine-1-phosphate receptor 1Migration[66]
S1PR219p13.2Sphingosine-1-phosphate receptor 2Migration[66]
S1PR39q22.1Sphingosine-1-phosphate receptor 3Migration[66]
S1PR519p13.2Sphingosine-1-phosphate receptor 5Migration[66]
SEMA3A7q21.11Semaphorin 3AMigration[61]
SEMA3F3p21.31Semaphorin 3FMigration; Proliferation[61]
SETDB11q21.3SET domain bifurcated histone lysine methyltransferase 1Differentiation[112]
SHH7q36.3Sonic hedgehog signaling moleculeSpecification; Migration; Proliferation[27,28,29,30,32,41]
SIRT110q21.3Sirtuin 1Differentiation[126]
SIRT219q13.2Sirtuin 2Differentiation[125]
SMARCA419p13.2SWI/SNF related, matrix associated, actin-dependent regulator of chromatin, subfamily a, member 4Specification; Differentiation[109,243]
SOD121q22.11Superoxide dismutase 1Proliferation; Differentiation[95]
SOX113q34SRY-box transcription factor 1Specification[33]
SOX23q26.33SRY-box transcription factor 2Specification; Proliferation; Differentiation[33,102,119]
SOX3Xq27.1SRY-box transcription factor 3Specification; Differentiation[33,119]
SOX512p12.1SRY-box transcription factor 5Migration; Proliferation; Differentiation[44]
SOX611p15.2SRY-box transcription factor 6Migration; Proliferation; Differentiation[44]
SOX816p13.3SRY-box transcription factor 8Specification; Differentiation[34,35,36,120]
SOX917q24.3SRY-box transcription factor 9Specification; Migration; Proliferation; Differentiation[36,44,82]
SOX1022q13.1SRY-box transcription factor 10Specification; Migration; Differentiation[43,44,122,281]
SOX112p25.2SRY-box transcription factor 11Differentiation[116]
SP712q13.13Sp7 transcription factorDifferentiation[243]
SREBF222q13.2Sterol regulatory element-binding transcription factor 2Differentiation[133]
STAT317q21.2Signal transducer and activator of transcription 3Differentiation[282]
SULF18q13.2-q13.3Sulfatase 1Specification[30]
TARDBP1p36.22TAR DNA binding proteinDifferentiation[134]
TCF418q21.2Transcription factor 4Differentiation[110]
TCF7L210q25.2-q25.3Transcription factor 7 like 2Differentiation[111]
THBS115q14Thrombospondin 1Migration[55]
THRA17q21.1Thyroid hormone receptor alphaDifferentiation[136,137,138]
TMEM9817q11.2Transmembrane protein 98Differentiation[195]
TNC9q33.1Tenascin CMigration; Proliferation[59,69]
TPPP5p15.33Tubulin polymerization promoting proteinProliferation; Differentiation[87]
TSPAN315q24.3Tetraspanin 3Migration; Proliferation[56]
VEGFA6p21.1Vascular endothelial growth factor AMigration; Proliferation[64,250]
WDR14p16.1WD repeat domain 1Differentiation[279]
YY114q32.2YY1 transcription factorDifferentiation[283]
ZBTB33Xq24Zinc finger and BTB domain containing 33Differentiation[111]
ZDHHC511q12.1Zinc finger DHHC-type palmitoyltransferase 5Differentiation[282]
ZEB22q22.3Zinc finger E-box binding homeobox 2Differentiation[284]
ZNF2418q12.2Zinc finger protein 24Differentiation[150]
* Data are retrieved from “The Human Protein Atlas” [285]. OPCs: Oligodendrocyte precursor cells.
Table A2. Regulators of axoglial interactions in myelin ensheathment.
Table A2. Regulators of axoglial interactions in myelin ensheathment.
Gene *Chromosomal Locus *Protein *Reference
CADM111q23.3Cell adhesion molecule 1[174]
CADM23p12.1Cell adhesion molecule 2[173,174]
CADM31q23.2Cell adhesion molecule 3[173]
CADM419q13.31Cell adhesion molecule 4[173]
CDH218q12.1Cadherin 2[165]
CNTN112q12Contactin 1[167,168,169,171]
CNTN21q32.1Contactin 2[172]
CNTNAP117q21.2Contactin-associated protein 1[167,168,169,170]
CNTNAP27q35–q36.1Contactin-associated protein 2[172]
EFNA11q22Ephrin A1[177]
EFNB213q33.3Ephrin B2[178]
EPHA42q36.1Ephrin receptor A4[177,178]
EPHB13q22.2Ephrin receptor B1[178]
JAM221q21.3Junctional adhesion molecule 2[181]
L1CAMXq28L1 cell adhesion molecule[166]
LINGO115q24.3Leucine rich repeat and Ig domain containing 1[143,179]
MAG19q13.12Myelin-associated glycoprotein[176]
NCAM111q23.2Neural cell adhesion molecule 1[180]
NRG18p12Neuregulin 1[286,287]
OLIG121q22.11Oligodendrocyte transcription factor 1[183]
ST3GAL216q22.1ST3 beta-galactoside alpha-2,3-sialyltransferase 2[175,176]
ST3GAL31p34.1ST3 beta-galactoside alpha-2,3-sialyltransferase 3[175,176]
WASL7q31.32WASP-like actin nucleation promoting factor[288,289]
* Data are retrieved from “The Human Protein Atlas” [285].
Table A3. Molecules implicated in myelin growth and preservation.
Table A3. Molecules implicated in myelin growth and preservation.
Gene *Chromosomal Locus *Protein *Reference
ABCD1Xq28ATP binding cassette subfamily D member 1[164,203]
AGPS2q31.2Alkylglycerone phosphate synthase[24,290]
CA28q21.2Carbonic anhydrase 2[291]
CLDN13q28Claudin 1[70]
CLDN37q11.23Claudin 3[70]
CLDN113q26.2Claudin 11[185]
CNP17q21.22′,3′-cyclic nucleotide 3′ phosphodiesterase[52,189]
DUSP1520q11.21Dual specificity phosphatase 15[247]
FGF15q31.3Fibroblast growth factor 1[198]
FGF24q28.1Fibroblast growth factor 2[198]
FGFR18p11.23Fibroblast growth factor receptor 1[197,198]
FGFR210q26.13Fibroblast growth factor receptor 2[197,198]
GAL3ST122q12.2Galactose-3-O-sulfotransferase 1[200]
GFAP17q21.31Glial fibrillary acidic protein[292]
GJB1Xq13.1Gap junction protein beta 1[161]
GJC21q42.13Gap junction protein gamma 2[161]
GNPAT1q42.2Glyceronephosphate O-acyltransferase[290]
HDAC35q31.3Histone deacetylase 3[199]
ID46p22.3Inhibitor of DNA binding 4, HLH protein[114]
MAG19q13.12Myelin-associated glycoprotein[147,186]
MAL2q11.1Mal, T cell differentiation protein[293]
MAP22q34Microtubule-associated protein 2[151]
MAPT17q21.31Microtubule-associated protein tau[151]
MBP18q23Myelin basic protein[52]
MOBP3p22.1Myelin-associated oligodendrocyte basic protein[190]
MOG6p22.1Myelin oligodendrocyte glycoprotein[187,188]
MYRF11q12.2Myelin regulatory factor[193]
NCAM111q23.2Neural cell adhesion molecule 1[294]
NKX2-220p11.22NK2 homeobox 2[194]
NKX2-68p21.2NK2 homeobox 6[194]
NPC118q11.2NPC intracellular cholesterol transporter 1[295]
OLIG121q22.11Oligodendrocyte transcription factor 1[183,196]
OLIG221q22.11Oligodendrocyte transcription factor 2[112,196]
OMG17q11.2Oligodendrocyte myelin glycoprotein[86,191,192]
OPALIN10q24.1Oligodendrocytic myelin paranodal and inner loop protein[204]
PEX512p13.31Peroxisomal biogenesis factor 5[202]
PLP1Xq22.2Proteolipid protein 1[184,185]
PROM14p15.32Prominin 1[296]
QKI6q26QKI, KH domain containing RNA binding[133]
SETDB11q21.3SET domain bifurcated histone lysine methyltransferase 1[112]
SOX816p13.3SRY-box transcription factor 8[35]
SOX1022q13.1SRY-box transcription factor 10[35,122]
SREBF222q13.2Sterol regulatory element-binding transcription factor 2[133]
TMEM9817q11.2Transmembrane protein 98[195]
TPPP5p15.33Tubulin polymerization promoting protein[297]
UGT84q26UDP glycosyltransferase 8[200,201]
* Data are retrieved from “The Human Protein Atlas” [285].


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Figure 1. Major cues of OPCs generation and differentiation during myelinogenesis in the prenatal period. In the neuroepithelium lining the neural tube, NSCs are under the influence of notochord-derived SHH, which drives the cells to become OPCs through OLIG2, SOX8/9/10 or follow neuronal fate (neuroblasts) via NGN1/2 and SOX1/2/3. BMP originated from the neural crest instructing NSCs to become astrocytes, controlled by HES1 as well. FOXJ1 is a crucial transcription factor for the ependymal trajectory. The positive and negative cues controlling OPCs differentiation are displayed in the upper right boxes. The hatched box depicts a representative area around sulcus limitans (between alar and basal plates). Dashed lines showcase naturally occurring processes, albeit not addressed in detail in the current review. ASCL1: Achaete-scute family bHLH transcription factor 1, BDNF: Brain-derived neurotrophic factor, BMP: Bone morphogenetic protein, CNTF: Ciliary neurotrophic factor, EGR1: Early growth response 1, EP: Ependymal cells, FOXJ1: Transcription factor forkhead box J1, GALC: Galactosylceramidase, GLI2: Glioma-associated oncogene family zinc finger 2, GPR17: G protein-coupled receptor 17, HES1: Hes family bHLH transcription factor 1, ID2: Inhibitor of DNA binding 2, ID4: Inhibitor of DNA binding 2, IGF-1: Insulin-like growth factor 1, JAG1: Jagged canonical Notch ligand 1, KLF6: Kruppel-like factor 6, MYRF: Myelin regulatory factor, NGN1: Neurogenin-1, NGN2: Neurogenin-2, NSC: Neural stem cells, NT-3: Neurotrophin 3, OL: Oligodendrocytes, OLIG1: Oligodendrocyte transcription factor 1, OLIG2: Oligodendrocyte transcription factor 2, OPC: Oligodendrocyte precursor cell, QKI: Quaking homolog, KH domain RNA binding, RG: Radial glia, SET domain bifurcated histone lysine methyltransferase 1, SETDB1: SHH: Sonic hedgehog signaling molecule, SIRT1: Sirtuin 1, SIRT2: Sirtuin 2, SOX: Sex-determining region Y-box transcription factor, SREBF2: Sterol regulatory element-binding transcription factor 2, T3: Triiodothyronine, TCF4: Transcription factor 4, ZFP191: Zinc finger protein 191.
Figure 1. Major cues of OPCs generation and differentiation during myelinogenesis in the prenatal period. In the neuroepithelium lining the neural tube, NSCs are under the influence of notochord-derived SHH, which drives the cells to become OPCs through OLIG2, SOX8/9/10 or follow neuronal fate (neuroblasts) via NGN1/2 and SOX1/2/3. BMP originated from the neural crest instructing NSCs to become astrocytes, controlled by HES1 as well. FOXJ1 is a crucial transcription factor for the ependymal trajectory. The positive and negative cues controlling OPCs differentiation are displayed in the upper right boxes. The hatched box depicts a representative area around sulcus limitans (between alar and basal plates). Dashed lines showcase naturally occurring processes, albeit not addressed in detail in the current review. ASCL1: Achaete-scute family bHLH transcription factor 1, BDNF: Brain-derived neurotrophic factor, BMP: Bone morphogenetic protein, CNTF: Ciliary neurotrophic factor, EGR1: Early growth response 1, EP: Ependymal cells, FOXJ1: Transcription factor forkhead box J1, GALC: Galactosylceramidase, GLI2: Glioma-associated oncogene family zinc finger 2, GPR17: G protein-coupled receptor 17, HES1: Hes family bHLH transcription factor 1, ID2: Inhibitor of DNA binding 2, ID4: Inhibitor of DNA binding 2, IGF-1: Insulin-like growth factor 1, JAG1: Jagged canonical Notch ligand 1, KLF6: Kruppel-like factor 6, MYRF: Myelin regulatory factor, NGN1: Neurogenin-1, NGN2: Neurogenin-2, NSC: Neural stem cells, NT-3: Neurotrophin 3, OL: Oligodendrocytes, OLIG1: Oligodendrocyte transcription factor 1, OLIG2: Oligodendrocyte transcription factor 2, OPC: Oligodendrocyte precursor cell, QKI: Quaking homolog, KH domain RNA binding, RG: Radial glia, SET domain bifurcated histone lysine methyltransferase 1, SETDB1: SHH: Sonic hedgehog signaling molecule, SIRT1: Sirtuin 1, SIRT2: Sirtuin 2, SOX: Sex-determining region Y-box transcription factor, SREBF2: Sterol regulatory element-binding transcription factor 2, T3: Triiodothyronine, TCF4: Transcription factor 4, ZFP191: Zinc finger protein 191.
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Figure 2. Axoglial driving cues for the initiation of ensheathment during myelinogenesis. A process of oligodendrocyte (blue) approaches the axon (brown) based on their surfaces’ attractive and repulsive signals. The red-colored shapes represent negative surface molecules; the green ones stand for positive and the yellow for bidirectional signals. For illustrational purposes, the paranode, juxtaparanode, and internode regions are simplified. CADM1b: Cell adhesion molecule 1b, CADM2: Cell adhesion molecule 2, CADM3: Cell adhesion molecule 3, CADM4: Cell adhesion molecule 4, CASPR: Contactin-associated protein, CASPR2: Contactin-associated protein-like 2, CNTN1: Contactin 1, EphA4: Ephrin receptor A4, EphB: Ephrin receptor B, EphB1: Ephrin receptor B1, GAL-4: Galectin-4, GD1a: Ganglioside GD1a, GT1b: Ganglioside GT1b, L1-CAM: L1 cell adhesion molecule, LINGO-1: Leucine-rich repeat and Ig-like domain-containing Nogo receptor interacting protein 1, MAG: Myelin-associated glycoprotein, NCAD: N-cadherin, NCAM: Neural cell adhesion molecule, NF155: Neurofascin 155, TAG-1: Transient axonal glycoprotein-1.
Figure 2. Axoglial driving cues for the initiation of ensheathment during myelinogenesis. A process of oligodendrocyte (blue) approaches the axon (brown) based on their surfaces’ attractive and repulsive signals. The red-colored shapes represent negative surface molecules; the green ones stand for positive and the yellow for bidirectional signals. For illustrational purposes, the paranode, juxtaparanode, and internode regions are simplified. CADM1b: Cell adhesion molecule 1b, CADM2: Cell adhesion molecule 2, CADM3: Cell adhesion molecule 3, CADM4: Cell adhesion molecule 4, CASPR: Contactin-associated protein, CASPR2: Contactin-associated protein-like 2, CNTN1: Contactin 1, EphA4: Ephrin receptor A4, EphB: Ephrin receptor B, EphB1: Ephrin receptor B1, GAL-4: Galectin-4, GD1a: Ganglioside GD1a, GT1b: Ganglioside GT1b, L1-CAM: L1 cell adhesion molecule, LINGO-1: Leucine-rich repeat and Ig-like domain-containing Nogo receptor interacting protein 1, MAG: Myelin-associated glycoprotein, NCAD: N-cadherin, NCAM: Neural cell adhesion molecule, NF155: Neurofascin 155, TAG-1: Transient axonal glycoprotein-1.
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Dermitzakis, I.; Manthou, M.E.; Meditskou, S.; Miliaras, D.; Kesidou, E.; Boziki, M.; Petratos, S.; Grigoriadis, N.; Theotokis, P. Developmental Cues and Molecular Drivers in Myelinogenesis: Revisiting Early Life to Re-Evaluate the Integrity of CNS Myelin. Curr. Issues Mol. Biol. 2022, 44, 3208-3237.

AMA Style

Dermitzakis I, Manthou ME, Meditskou S, Miliaras D, Kesidou E, Boziki M, Petratos S, Grigoriadis N, Theotokis P. Developmental Cues and Molecular Drivers in Myelinogenesis: Revisiting Early Life to Re-Evaluate the Integrity of CNS Myelin. Current Issues in Molecular Biology. 2022; 44(7):3208-3237.

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Dermitzakis, Iasonas, Maria Eleni Manthou, Soultana Meditskou, Dimosthenis Miliaras, Evangelia Kesidou, Marina Boziki, Steven Petratos, Nikolaos Grigoriadis, and Paschalis Theotokis. 2022. "Developmental Cues and Molecular Drivers in Myelinogenesis: Revisiting Early Life to Re-Evaluate the Integrity of CNS Myelin" Current Issues in Molecular Biology 44, no. 7: 3208-3237.

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