Oligodendrocytes develop from precursor cells that migrate throughout the spinal cord and brain before differentiating and enwrapping axons. Oligodendrocyte precursors (OLPs) are generated from neuroepithelial cells that line the central canal of the spinal cord and the ventricles of the brain. Where exactly the OLPs originate in the ventricular zone (VZ) has been a contentious issue, which is now being resolved through the application of mouse genetics.
The 'classic' view was that gliogenesis was the default behaviour of all neuroepithelial cells after they had finished giving rise to neurons. Later, a specialized OLP 'factory' was discovered in the ventral VZ of the spinal cord; this neuroepithelial domain (pMN) first generates motor neurons before switching to OLPs. Master regulatory genes (oligodendrocyte transcription factors Olig1 and Olig2) that control both motor neuron and OLP production are also expressed in the ventral forebrain, which suggests that ventral production of OLPs is the norm. However, a series of recent articles has debunked this idea by showing that they are widely generated through the VZ of the spinal cord and brain. In the spinal cord, most OLPs are produced in the pMN, but a minority (∼15%) come from more dorsal parts of the VZ. In the forebrain, OLPs are generated from different parts of the embryonic VZ at different times, starting in the ventral forebrain and progressing dorsally into the cerebral cortex. Surprisingly, the earliest-formed OLPs and their progeny are eliminated during postnatal life.
Specification of ventrally-derived OLPs requires sonic hedgehog (SHH). However, OLPs from dorsal sources are hedgehog-independent, instead relying on fibroblast growth factor (FGF) and other local signals. Whether this implies that there are different functional subtypes of oligodendrocytes is not clear.
In the forebrain, OLPs intermix and compete with one another for territory. This is evident from the observation that if OLPs from one part of the VZ are ablated in transgenic mice, the remaining OLPs quickly expand into the empty space and the mice survive and behave normally. This implies that there are no major functional differences among OLPs in the forebrain, even though they begin by expressing different region-specific transcription factors such as Nkx2.1, Gsh2 or Emx1.
There is some evidence that OLPs are generated only from ventral territories in birds. Why should they differ from mammals? We propose that ventral production was the 'primitive' mode and that recruitment of more dorsal sources was required as the brain, particularly the cerebral cortex, increased in size during vertebrate evolution.
Oligodendrocyte precursors first arise in a restricted ventral part of the embryonic spinal cord and migrate laterally and dorsally from there. Later, secondary sources develop in the dorsal cord. Normally, the ventrally-derived precursors compete with and suppress their dorsal counterparts. There are also ventral and dorsal sources in the forebrain, but here the more dorsal precursors prevail and the ventral-most lineage is eliminated during postnatal life. How do the different populations compete and what is the outcome of the competition? Do different embryonic origins signify different functional subgroups of oligodendrocyte?
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We would like to thank our colleagues, past and present, for their individual scientific contributions and tremendous fun. We also thank our fellow scientists across the world — some named in this article — for stimulation and collaboration. Work in the authors' laboratory has been supported by the UK Medical Research Council (MRC), the Wellcome Trust and the European Union. N.K. is supported by the Wellcome Trust Functional Genomics Initiative and N.P. by a programme grant from the MRC.
The authors declare no competing financial interests.
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Richardson, W., Kessaris, N. & Pringle, N. Oligodendrocyte wars. Nat Rev Neurosci 7, 11–18 (2006). https://doi.org/10.1038/nrn1826
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