Role of Shh and Gli Signalling in Oligodendroglial Development

Part of the Molecular Biology Intelligence Unit book series (MBIU)


Recent molecular and genetic studies have demonstrated that early oligodendrocyte progenitor cells are induced from the ventral neural tube by the Sonic hedgehog (Shh) protein produced in the ventral midline structures. Whilst Shh signalling is required for ventral oligodendrogenesis in the entire central nervous system, Gli2 activity only regulates oligodendrocyte development in the ventral spinal cord. Gli3 plays a nonessential role in ventral oligodendrogenesis during normal development. However, in the absence of Shh signalling, Gli3 functions as a repressor of ventral oligodendrogenesis. In addition, there is growing evidence that a separate population of oligodendrocyte progenitor cells is also produced from the dorsal region of the neural tube independent of Shh signalling.


Sonic Hedgehog Floor Plate Dorsal Spinal Cord Oligodendrocyte Differentiation Oligodendrocyte Lineage 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Noll E, Miller R. Oligodendrocyte precursors originate at the ventral ventricular zone dorsal to the ventral midline region in the embryonic rat spinal cord. Development 1993; 118:563–573.PubMedGoogle Scholar
  2. 2.
    Pringle N, Richardson W. 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; 117:525–533.PubMedGoogle Scholar
  3. 3.
    Timsit S, Martinez S, Allinquant B et al. Oligodendrocytes originate in a restricted zone of the embryonic ventral neural tube defined by DM-20 mRNA expression. J Neurosci 1995; 15:1012–1024.PubMedGoogle Scholar
  4. 4.
    Warf B, Fok-Seang J, Miller R. Evidence for the ventral origin of oligodendrocyte precursors in the rat spinal cord. J Neurosci 1991; 11:2477–2488.PubMedGoogle Scholar
  5. 5.
    Pringle N, Guthrie S, Lumsden A et al. Dorsal spinal cord neuroepithelium generates astrocytes but not oligodendrocytes. Neuron 1998; 20:883–93.PubMedCrossRefGoogle Scholar
  6. 6.
    Sussman CR, Dyer KL, Marchionni M et al. Local control of oligodendrocyte development in isolated dorsal mouse spinal cord. J Neurosci Res 2000; 59:413–420.PubMedCrossRefGoogle Scholar
  7. 7.
    Sun T, Pringle NP, Hardy AP et al. Pax-6 influences the time and site of origin of glial precursors in the ventral neural tube. Mol Cell Neurosci 1998; 12:228–239.PubMedCrossRefGoogle Scholar
  8. 8.
    Lu Q, Yuk D, Alberta J et al. Sonic Hedgehog-regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. Neuron 2000; 25:317–329.PubMedCrossRefGoogle Scholar
  9. 9.
    Takebayashi H, Yoshida S, Sugimori M et al. Dynamic expression of basic helix-loop-helix Olig family members: Implication of Olig2 in neuron and oligodendrocyte differentiation and identification of a new member, Olig3. Mech Dev 2000; 99:143–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhou Q, Wang S, Anderson DJ. Identification of a novel family of oligodendrocyte lineage-specific basic helix-loop-helix transcription factors. Neuron 2000; 25:331–343.PubMedCrossRefGoogle Scholar
  11. 11.
    Fu H, Qi Y, Tan 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; 129:681–693.PubMedGoogle Scholar
  12. 12.
    Zhou Q, Choi G, Anderson DJ. The bHLH transcription factor Olig2 promotes oligodendrocyte differentiation in collaboration with Nkx2.2. Neuron 2001; 31:791–807.PubMedCrossRefGoogle Scholar
  13. 13.
    Lu Q, Sun T, Zhu Z et al. Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell 2002; 109:75–86.PubMedCrossRefGoogle Scholar
  14. 14.
    Takebayashi H, Nabeshima Y, Yoshida S et al. The basic helix-loop-helix factor olig2 is essential for the development of motoneuron and oligodendrocyte lineages. Curr Biol 2002; 12:1157–1163.PubMedCrossRefGoogle Scholar
  15. 15.
    Zhou Q, Anderson DJ. The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell 2002; 109:61–73.PubMedCrossRefGoogle Scholar
  16. 16.
    Richardson W, Pringle N, Yu W et al. Origins of spinal cord oligodendrocytes: Possible developmental and evolutionary relationships with motor neurons. Dev Neurosci 1997; 19:58–68.PubMedCrossRefGoogle Scholar
  17. 17.
    Richardson W, Smith H, Sun T et al. Oligodendrocyte lineage and the motor neuron connection Glia 2000; 29:136–142.PubMedCrossRefGoogle Scholar
  18. 18.
    Arnett H, Fancy S, Alberta J et al. bHLH transcription factor Oligl is required to repair demyelinated lesions in the CNS. Science 2004; 306:2111–2115.PubMedCrossRefGoogle Scholar
  19. 19.
    Jessell TM. Neuronal specification in the spinal cord: Inductive signals and transcriptional codes. Nat Rev Genet 2000; 1:20–29.PubMedCrossRefGoogle Scholar
  20. 20.
    Echelard Y, Epstein D, St-Jacques B et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 1993; 75:1417–1430.PubMedCrossRefGoogle Scholar
  21. 21.
    Roelink H, Porter J, Chiang C et al. Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis. Cell 1995; 81:445–455.PubMedCrossRefGoogle Scholar
  22. 22.
    Orentas D, Miller R. Regulation of oligodendrocyte development. Mol Neurobiol 1999; 18:247–259.CrossRefGoogle Scholar
  23. 23.
    Trousse F, Giess M, Soula C et al. Notochord and floor plate stimulate oligodendrocyte differentiation in cultures of the chick dorsal neural tube. J Neurosci Res 1995; 41:552–560.PubMedCrossRefGoogle Scholar
  24. 24.
    Poncet C, Soula C, Trousse F et al. Induction of oligodendrocyte progenitors in the trunk neural tube by ventralizing signals: Effects of notochord and floor plate grafts, and of sonic hedgehog. Mech Dev 1996; 60:13–32.PubMedCrossRefGoogle Scholar
  25. 25.
    Pringle N, Yu W, Guthrie S et al. Determination of neuroepithelial cell fate: Induction of the oligodendrocyte lineage by ventral midline cells and sonic hedgehog. Dev Biol 1996; 177:30–42.PubMedCrossRefGoogle Scholar
  26. 26.
    Orentas D, Hayes J, Dyer K et al. Sonic hedgehog signaling is required during the appearance of spinal cord oligodendrocyte precursors. Development 1999; 126:2419–29.PubMedGoogle Scholar
  27. 27.
    Chandran S, Kato H, Gerreli D et al. FGF-dependent generation of oligodendrocytes by a hedgehog-independent pathway. Development 2003; 130:6599–6609.PubMedCrossRefGoogle Scholar
  28. 28.
    Cai J, Qi Y, Hu X et al. Generation of oligodendrocyte precursor cells from mouse dorsal spinal cord independent of Nkx6-regulation and Shh signaling. Neuron 2005; 45:41–53.PubMedCrossRefGoogle Scholar
  29. 29.
    Qi Y, Stapp D, Qiu M. Origin and molecular specification of oligodendrocytes in the telencephalon. TINS 2002; 25:223–225.PubMedGoogle Scholar
  30. 30.
    Olivier C, Cobos I, Villegas E et al. Monofocal origin of telencephalic oligodendrocytes in the anterior entopeduncular area of the chick embryo. Development 2001; 128:1757–1769.PubMedGoogle Scholar
  31. 31.
    Nery S, Wichterle H, Fishell G. Sonic hedgehog contributes to oligodendrocyte specification in the mammalian forebrain. Development 2001; 128:527–540.PubMedGoogle Scholar
  32. 32.
    Tekki-Kessaris N, Woodruff R, Hall A et al. Hedgehog-dependent oligodendrocyte lineage specification in the telencephalon. Development 2001; 128:2545–2554.PubMedGoogle Scholar
  33. 33.
    Alberta J, Park S-K, Mora J et al. Sonic hedgehog is required during an early phase of oligodendrocyte development in mammalian brain. Mol Cell Neurosci 2001; 18:434–441.PubMedCrossRefGoogle Scholar
  34. 34.
    Davies JE, Miller RH. Local sonic hedgehog signaling regulates oligodendrocyte precursor appearance in multiple ventricular zone domains in the chick metencephalon. Dev Biol 2001; 233:513–525.PubMedCrossRefGoogle Scholar
  35. 35.
    Vallstedt A, Klos J, Ericson J. Multiple dorsoventral origins of oligodendrocyte generation in the spinal cord and hindbrain. Neuron 2005; 45:55–67.PubMedCrossRefGoogle Scholar
  36. 36.
    Miller RH. Dorsally derived oligodendrocytes come of age. Neuron 2005; 45:1–3.PubMedCrossRefGoogle Scholar
  37. 37.
    Kessaris N, Jamen F, Rubin L et al. Cooperation between sonic hedgehog and fibroblast growth factor/MAPK signaling pathways in neocortical precursors. Development 2004; 131:1289–1298.PubMedCrossRefGoogle Scholar
  38. 38.
    Wijgerde M, McMahon J, Rule M et al. A direct requirement for Hedgehog signaling for normal specification of all ventral progenitor domains in the presumptive mammalian spinal cord. Genes Dev 2002; 16:2849–2864.PubMedCrossRefGoogle Scholar
  39. 39.
    Gabay L, Lowell S, Rubin L et al. Deregulation of dorsoventral patterning by FGF confers trilineage differentiation capacity on CNS stem cells in vitro. Neuron 2003; 40:485–499.PubMedCrossRefGoogle Scholar
  40. 40.
    Mekki-Dauriac S, Agius E, Kan P et al. Bone morphogenetic proteins negatively control oligodendrocyte precursor specification in the chick spinal cord. Development 2002; 129:5117–5130.PubMedGoogle Scholar
  41. 41.
    Hui CC, Slusarski D, Platt K et al. Expression of three mouse homologs of the Drosophila segment polarity gene cubitus interruptus, Gli, Gli-2, and Gli-3, in ectoderm-and mesoderm-derived tissues suggests multiple roles during postimplantation development. Dev Biol 1994; 162:402–13.PubMedCrossRefGoogle Scholar
  42. 42.
    Lei Q, Zelman AK, Kuang E et al. Transduction of graded Hedgehog signaling by a combination of Gli2 and Gli3 activator functions in the developing spinal cord. Development 2004; 131:3593–3604.PubMedCrossRefGoogle Scholar
  43. 43.
    Bai C, Stephen D, Joyner AL. All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev Cell 2004; 6:103–115.PubMedCrossRefGoogle Scholar
  44. 44.
    Ruiz I Altaba A, Palma V, Dahmane N. Hedgehog-Gli signalling and the growth of the brain. Nat Rev Neurosci 2002; 3:24–33.PubMedCrossRefGoogle Scholar
  45. 45.
    Lee J, Platt KA, Censullo P et al. Glil is a target of Sonic hedgehog that induces ventral neural tube development. Development 1997; 124:2537–2552.PubMedGoogle Scholar
  46. 46.
    Ruiz I Altaba A. Combinatorial Gli gene function in floor plate and neuronal inductions by Sonic hedgehog. Development 1998; 125:2203–2212.PubMedGoogle Scholar
  47. 47.
    Bai C, Joyner AL. Glil can rescue the in vivo function of Gli2. Development 2001; 128:5161–5172.PubMedGoogle Scholar
  48. 48.
    Ding Q, Motoyama J, Gasca S et al. Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice. Development 1998; 125:2533–2543.PubMedGoogle Scholar
  49. 49.
    Matise M, Epstein D, Park H et al. Gli2 is required for induction of floor plate and adjacent cells, but not most ventral neurons in the mouse central nervous system. Development 1998; 125:2759–2770.PubMedGoogle Scholar
  50. 50.
    Park H, Bai C, Platt K et al. Mouse Glil mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development 2000; 127:1593–605.PubMedGoogle Scholar
  51. 51.
    Litingtung Y, Chiang C. Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3. Nat Neurosci 2000; 3:979–985.PubMedCrossRefGoogle Scholar
  52. 52.
    Tyurina O, Guner B, Popova E et al. Zebrafish Gli3 functions as both an activator and a repressor in Hedgehog signaling. Dev Biol 2005; 277:537–556.PubMedCrossRefGoogle Scholar
  53. 53.
    Persson M, Stamataki D, Welscher P et al. Dorsal-ventral patterning of the spinal cord requires Gli3 transcriptional repressor activity. Genes Dev 2002; 16:2865–2878.PubMedCrossRefGoogle Scholar
  54. 54.
    Motoyama J, Milenskovic L, Iwama M et al. Differential requirement for Gli2 and Gli3 in ventral neural cell fate specification. Dev Biol 2003; 259:150–161.PubMedCrossRefGoogle Scholar
  55. 55.
    Qi Y, Tan M, Hui C-C et al. GH2 activity is required for normal Shh signaling and oligodendrocyte development. Mol Cell Neurosci 2003; 23:440–450.PubMedCrossRefGoogle Scholar
  56. 56.
    Bitgood MJ, McMahon AP. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev Biol 1995; 172:126–138.PubMedCrossRefGoogle Scholar
  57. 57.
    Liu R, Cai J, Hu X et al. Region-specific and stage-dependent regulation of Olig gene expression and oligodendrogenesis by Nkx6.1 homeodomain transcription factor. Development 2003; 130:6221–6231.PubMedCrossRefGoogle Scholar
  58. 58.
    Temple S, Raff M. Clonal analysis of oligodendrocyte development in culture: Evidence for a developmental clock that counts cell divisions. Cell 1986; 44:773–779.PubMedCrossRefGoogle Scholar
  59. 59.
    Gao FB, Durand B, Raff M. Oligodendrocyte precursor cells count time but not cell divisions before differentiation. Curr Biol 1997; 7:152–155.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2006

Authors and Affiliations

  1. 1.Department of Anatomical Sciences and Neurobiology, School of MedicineUniversity of LouisvilleLouisvilleUSA

Personalised recommendations