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By changing the composition of CSF or the blood stream, Table 1: Main modulators of oligodendrogenesis in the
it would be possible to modulate proliferation and or adult brain
differentiation of SVZ progenitors with an impact on Signal Effect
demyelinating diseases; however, these modifications Extrinsic
should be tightly regulated to maintain brain homeostasis. Morphogens
Wnt [62] Stimulates NSC proliferation/self-renewal
Notch [63,64] Required for NSC proliferation,
MODULATORS OF OLIGODENDROGENESIS maintenance
Shh [65] Required for NSC maintenance and
Extrinsic factors [58] OPC production
The extrinsic factors include morphogens, growth SIRT1 Inhibits oligodendrogenesis
Inhibits oligodendrogenesis
BMP
[66]
factors, and signaling molecules delivered through Growth factors
blood vessels or associated with the extracellular EGF [67] Stimulates OPC proliferation and
matrix. For instance, during the development of both FGF‑2 [68] migration
Induces progenitor cell proliferation
the brain and spinal cord, the relative levels of Sonic IGF‑1 [61] Stimulates oligodendrocyte differentiation
hedgehog (Shh), BMP, and Wnt/β‑catenin have been PDGF [58] Induces OPC proliferation and
shown to play roles in oligodendrocyte determination. Extracellular matrix differentiation
[1]
The motoneuron domain (pMN) is a restricted domain elements
of the ventral ventricular zone of the embryonic Laminin [56] Promotes OPC generation
spinal cord, and in mice, cells in this domain express Intrinsic
Transcription factors
the transcription factors Olig1 and Olig2. [50] In this ASCL1 [69] Favors oligodendrocyte fate
zone, Olig2 expression is crucial for the production Nkx6.1/6.2 [70,71] Required for oligodendrocyte and
of motoneurons and oligodendrocytes. In order for Sox8/9 [72] motoneuron production in the pMN
Promotes glial specification
this transcription factor to induce oligodendrogenic Epigenetic markers
cell fate instead of neuronal differentiation, a switch miRNA-7a [73] [74] Promotes OPC commitment
[1]
must occur. As seen in both mice and zebrafish, this Histone methylation [75] Favors OPC production
Inhibits OPC differentiation
Histone acetylation
switch is highly dependent on the level of Shh in the NSC: neural stem cell; OPC: oligodendrocyte precursor cell; pMN: progenitors
environment and on the Notch/delta pathway, which of motor neurons; Shh: sonic hedgehog; BMP: bone morphogenic protein;
[51]
restricts the production of motoneurons, thus allowing EGF: epidermal growth factor; FGF‑2: fibroblast growth factor‑2; IGF‑1: insulin‑like
growth factor‑1; PDGF: platelet‑derived growth factor; ASCL1: achaete‑scute
oligodendrocyte determination. On the other hand, homolog 1
[52]
this switch is repressed if high level of BMPs and Wnt
are locally present. It has also been shown that, during regulators. The main transcription factor involved in
[53]
brain development, Shh promotes the generation of oligodendrocyte determination is Olig2. This basic
[76]
ventrally derived OPCs, [11] while Wnt/β‑catenin and helix‑loop‑helix (bHLH) factor is induced by Shh and
BMPs inhibit it. Curiously, in the adult brain, there is an expressed in every stage of oligodendrocyte maturation,
[1]
apparent contradiction since Wnt3 (from the Wnt family) from OPC to myelinating oligodendrocyte. In the
promotes oligodendrocyte specification in the SVZ. [13] majority of the CNS, inactivation of Olig2 during
development leads to a reduction in OPCs. [76‑78] In
Other extrinsic factors modulate oligodendrogenesis contrast, overexpression of Olig2 in neuroepithelium
in the adult SVZ. Evidence shows that both factors leads to enhanced OPC production in the CNS. [79]
secreted by blood vessels and factors connected to Furthermore, the presence of Olig2 is sufficient to
the extracellular matrix are capable of favoring OPC reprogram rat and mouse fibroblasts into induced
commitment. [13,54,55] One of these factors is laminin, an OPCs. [80,81] Although this factor is crucial to
element of the extracellular matrix. A study in mice oligodendrocyte differentiation, Olig2 knockout mice
shows that the elimination of laminin α2‑subunit are still able to produce some OPCs in the hindbrain,
leads to a reduction of the OPC population in the possibly through Olig1 compensation. [76]
SVZ. [56] Other trophic factors, such as PDGF [57,58]
and epidermal growth factor (EGF), [59,60] contribute Another important transcription factor is Achaete‑scute
indirectly to oligodendrocyte lineage determination, homolog 1 (Ascl1 or Mash1), which is also a bHLH
[1]
through promoting OPC proliferation and factor. During development, absence of Ascl1 leads
maturation. Additionally, IGF‑1 also contributes to to a reduction of OPC production in the brain and
oligodendrogenesis by blocking BMP signaling, both spinal cord. [82,83] However, this reduction can be
in vivo and in vitro [Table 1]. [61] compensated to normal values by Ascl2 and 3. [83] After
birth, Ascl1 is only expressed in C cells and OPCs in
Intrinsic factors the SVZ [69] and similarly to what happens during CNS
The intrinsic factors that modulate oligodendrogenesis development, elimination of this transcription factor
include transcription factors and epigenetic leads to decreased OPC generation. [69]

268 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 269