Genetic Evidence that Dorsal Spinal Oligodendrocyte Progenitor Cells are Capable of Myelinating Ventral Axons Effectively in Mice


In the developing spinal cord, the majority of oligodendrocyte progenitor cells (OPCs) are induced in the ventral neuroepithelium under the control of the Sonic Hedgehog (Shh) signaling pathway, whereas a small subset of OPCs are generated from the dorsal neuroepithelial cells independent of the Shh pathway. Although dorsally-derived OPCs (dOPCs) have been shown to participate in local axonal myelination in the dorsolateral regions during development, it is not known whether they are capable of migrating into the ventral region and myelinating ventral axons. In this study, we confirmed and extended the previous study on the developmental potential of dOPCs in the absence of ventrally-derived OPCs (vOPCs). In Nestin-Smo conditional knockout (cKO) mice, when ventral oligodendrogenesis was blocked, dOPCs were found to undergo rapid amplification, spread to ventral spinal tissue, and eventually differentiated into myelinating OLs in the ventral white matter with a temporal delay, providing genetic evidence that dOPCs are capable of myelinating ventral axons in the mouse spinal cord.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6


  1. 1.

    Emery B. Regulation of oligodendrocyte differentiation and myelination. Science 2010, 330: 779–782.

    CAS  Article  Google Scholar 

  2. 2.

    Gallo V, Deneen B. Glial development: the crossroads of regeneration and repair in the CNS. Neuron 2014, 83: 283308.

    CAS  Article  Google Scholar 

  3. 3.

    Foerster S, Hill MFE, Franklin RJM. Diversity in the oligodendrocyte lineage: Plasticity or heterogeneity? Glia 2019, 67: 17971805.

    PubMed  Google Scholar 

  4. 4.

    Pringle NP, Richardson WD. A singularity of PDGF alpha-receptor expression in the dorsoventral axis of the neural tube may define the origin of the oligodendrocyte lineage. Development 1993, 117: 525533.

    CAS  Google Scholar 

  5. 5.

    Pringle NP, Yu WP, Guthrie S, Roelink H, Lumsden A, Peterson AC, et al. Determination of neuroepithelial cell fate: induction of the oligodendrocyte lineage by ventral midline cells and sonic hedgehog. Dev Biol 1996, 177: 3042.

    CAS  Article  Google Scholar 

  6. 6.

    Cai J, Qi Y, Hu X, Tan M, Liu Z, Zhang J, et al. Generation of oligodendrocyte precursor cells from mouse dorsal spinal cord independent of Nkx6 regulation and Shh signaling. Neuron 2005, 45: 4153.

    CAS  Article  Google Scholar 

  7. 7.

    Fogarty M, Richardson WD, Kessaris N. A subset of oligodendrocytes generated from radial glia in the dorsal spinal cord. Development 2005, 132: 19511959.

    CAS  Article  Google Scholar 

  8. 8.

    Vallstedt A, Klos JM, Ericson J. Multiple dorsoventral origins of oligodendrocyte generation in the spinal cord and hindbrain. Neuron 2005, 45: 5567.

    CAS  Article  Google Scholar 

  9. 9.

    Tripathi RB, Clarke LE, Burzomato V, Kessaris N, Anderson PN, Attwell D, et al. Dorsally and ventrally derived oligodendrocytes have similar electrical properties but myelinate preferred tracts. J Neurosci 2011, 31: 68096819.

    CAS  Article  Google Scholar 

  10. 10.

    Zhu Q, Whittemore SR, Devries WH, Zhao XF, Kuypers NJ, Qiu MS. Dorsally-derived oligodendrocytes in the spinal cord contribute to axonal myelination during development and remyelination following focal demyelination. Glia 2011, 59: 16121621.

    Article  Google Scholar 

  11. 11.

    Crawford AH, Tripathi RB, Richardson WD, Franklin RJM. Developmental origin of oligodendrocyte lineage cells determines response to demyelination and susceptibility to age-associated functional decline. Cell Rep 2016, 15: 761773.

    CAS  Article  Google Scholar 

  12. 12.

    Yu K, McGlynn S, Matise MP. Floor plate-derived sonic hedgehog regulates glial and ependymal cell fates in the developing spinal cord. Development 2013, 140: 15941604.

    CAS  Article  Google Scholar 

  13. 13.

    Zhang XM, Ramalho-Santos M, McMahon AP. Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R symmetry by the mouse node. Cell 2001, 106: 781792.

    CAS  Article  Google Scholar 

  14. 14.

    Schaeren-Wiemers N, Gerfin-Moser A. A single protocol to detect transcripts of various types and expression levels in neural tissue and cultured cells: in situ hybridization using digoxigenin-labelled cRNA probes. Histochemistry 1993, 100: 431440.

    CAS  Article  Google Scholar 

  15. 15.

    Shen YT, Gu Y, Su WF, Zhong JF, Jin ZH, Gu XS, et al. Rab27b is involved in lysosomal exocytosis and proteolipid protein trafficking in oligodendrocytes. Neurosci Bull 2016, 32: 331340.

    CAS  Article  Google Scholar 

  16. 16.

    Xu X, Yu Q, Fang M, Yi M, Yang A, Xie B, et al. Stage-specific regulation of oligodendrocyte development by Hedgehog signaling in the spinal cord. Glia 2020, 68: 422434.

    Article  Google Scholar 

  17. 17.

    Stolt CC, Lommes P, Sock E, Chaboissier MC, Schedl A, Wegner M. The Sox9 transcription factor determines glial fate choice in the developing spinal cord. Genes Dev 2003, 17: 16771689.

    CAS  Article  Google Scholar 

  18. 18.

    Jiang C, Yang W, Fan Z, Teng P, Mei R, Yang J, et al. AATYK is a novel regulator of oligodendrocyte differentiation and myelination. Neurosci Bull 2018, 34: 527533.

    CAS  Article  Google Scholar 

  19. 19.

    Ge X, Xiao G, Huang H, Du J, Tao Y, Yang A, et al. Stage-dependent regulation of oligodendrocyte development and enhancement of myelin repair by dominant negative Master-mind 1 protein. Glia 2019, 67: 16541666.

    PubMed  Google Scholar 

  20. 20.

    Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 1996, 383: 407413.

    CAS  Article  Google Scholar 

  21. 21.

    Tan M, Hu X, Qi Y, Park J, Cai J, Qiu M. Gli3 mutation rescues the generation, but not the differentiation, of oligodendrocytes in Shh mutants. Brain Res 2006, 1067: 158163.

    CAS  Article  Google Scholar 

  22. 22.

    Wijgerde M, McMahon JA, Rule M, McMahon AP. A direct requirement for Hedgehog signaling for normal specification of all ventral progenitor domains in the presumptive mammalian spinal cord. Genes Dev 2002, 16: 28492864.

    CAS  Article  Google Scholar 

  23. 23.

    Stolt CC, Rehberg S, Ader M, Lommes P, Riethmacher D, Schachner M, et al. Terminal differentiation of myelin-forming oligodendrocytes depends on the transcription factor Sox10. Genes Dev 2002, 16: 165170.

    CAS  Article  Google Scholar 

  24. 24.

    Zhu Q, Zhao X, Zheng K, Li H, Huang H, Zhang Z, et al. Genetic evidence that Nkx2.2 and Pdgfra are major determinants of the timing of oligodendrocyte differentiation in the developing CNS. Development 2014, 141: 548555.

  25. 25.

    Emery B, Agalliu D, Cahoy JD, Watkins TA, Dugas JC, Mulinyawe SB, et al. Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination. Cell 2009, 138: 172185.

    CAS  Article  Google Scholar 

  26. 26.

    Huang H, Teng P, Du J, Meng J, Hu X, Tang T, et al. Interactive repression of MYRF self-cleavage and activity in oligodendrocyte differentiation by TMEM98 protein. J Neurosci 2018, 38: 98299839.

    CAS  Article  Google Scholar 

  27. 27.

    Fu H, Qi Y, Tan M, Cai J, Takebayashi H, Nakafuku M, et al. Dual origin of spinal oligodendrocyte progenitors and evidence for the cooperative role of Olig2 and Nkx2.2 in the control of oligodendrocyte differentiation. Development 2002, 129: 681693.

    CAS  Google Scholar 

  28. 28.

    Qi Y, Cai J, Wu Y, Wu R, Lee J, Fu H, et al. Control of oligodendrocyte differentiation by the Nkx2.2 homeodomain transcription factor. Development 2001, 128: 27232733.

    CAS  PubMed  Google Scholar 

  29. 29.

    Zhou Q, Choi G, Anderson DJ. The bHLH transcription factor Olig2 promotes oligodendrocyte differentiation in collaboration with Nkx2.2. Neuron 2001, 31: 791807.

    CAS  Article  Google Scholar 

  30. 30.

    Kessaris N, Fogarty M, Iannarelli P, Grist M, Wegner M, Richardson WD. Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage. Nat Neurosci 2006, 9: 173179.

    CAS  Article  Google Scholar 

  31. 31.

    Naruse M, Ishizaki Y, Ikenaka K, Tanaka A, Hitoshi S. Origin of oligodendrocytes in mammalian forebrains: a revised perspective. J Physiol Sci 2017, 67: 6370.

    CAS  Article  Google Scholar 

  32. 32.

    Richardson WD, Kessaris N, Pringle N. Oligodendrocyte wars. Nat Rev Neurosci 2006, 7: 1118.

    CAS  Article  Google Scholar 

Download references


This work was supported by the Natural Science Foundation of Zhejiang Province, China (LQ17C040001, LQ20C090004, and LQ18C090005) and the National Natural Science Foundation of China (31871480, 81771028, and 31771621).

Author information



Corresponding authors

Correspondence to Mengsheng Qiu or Xiaofeng Xu.

Ethics declarations

Conflict of interest

All authors claim that there are no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 1640 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fang, M., Yu, Q., Ou, B. et al. Genetic Evidence that Dorsal Spinal Oligodendrocyte Progenitor Cells are Capable of Myelinating Ventral Axons Effectively in Mice. Neurosci. Bull. (2020).

Download citation


  • Dorsally-derived OPCs
  • OPC proliferation
  • Oligodendrocyte differentiation
  • Myelination