Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development

Nature Reviews Neuroscience volume 7, pages 772–783 (2006)Cite this article

A Corrigendum to this article was published on 01 November 2006

Key Points

  • Hedgehog signalling in the mammalian nervous system has been traditionally associated with dorsoventral patterning. Many recent findings have demonstrated its involvement in various temporally regulated developmental processes. This review provides an overview of the spatial and temporal contexts in which hedgehog signalling is utilized.

  • We outline the basic hedgehog signalling pathway and discuss the roles of newly identified regulators of this pathway, including extracellular mediators (such as IHOG) and a family of genes associated with cilia function.

  • The review describes the core molecular components utilized in the establishment of ventral patterning in the spinal cord. We then discuss the role of hedgehog signalling in ventral patterning in the broader context of its role at various more anterior levels of the neuraxis, including the forebrain, midbrain and hindbrain.

  • A number of non-patterning functions of hedgehog signalling have been discovered, including a role in the specification of oligodendrocyte precursors, as well as the regulation of embryonic proliferation and apoptosis.

  • An unforeseen role for hedgehog signalling in ventral midline axonal guidance has been uncovered. Intriguingly, the time course of events suggests this is mediated by non-canonical signalling.

  • Recently, hedgehog signalling has been shown to be active in adult neural stem cells and to be required for the maintenance of the telencephalic progenitor cell niche.

Abstract

Sonic hedgehog has received an enormous amount of attention since its role as a morphogen that directs ventral patterning in the spinal cord was discovered a decade ago. Since that time, a bewildering array of information has been generated concerning both the components of the hedgehog signalling pathway and the remarkable number of contexts in which it functions. Nowhere is this more evident than in the nervous system, where hedgehog signalling has been implicated in events as disparate as axonal guidance and stem cell maintenance. Here we review our present knowledge of the hedgehog signalling pathway and speculate about areas in which further insights into this versatile pathway might be forthcoming.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The vertebrate hedgehog signalling pathway.
Figure 2: Sonic hedgehog gradients are translated into unique cell identities through the modulation of GLI activators and repressors.
Figure 3: The utilization of sonic hedgehog differs across the developing neuraxis.
Figure 4: SHH signalling functions in a number of distinct contexts in neural development.

Similar content being viewed by others

References

  1. Huangfu, D. & Anderson, K. V. Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development 133, 3–14 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Ingham, P. W. & McMahon, A. P. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15, 3059–3087 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Jessell, T. M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nature Rev. Genet. 1, 20–29 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Ashe, H. L. & Briscoe, J. The interpretation of morphogen gradients. Development 133, 385–394 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Aza-Blanc, P., Ramirez-Weber, F. A., Laget, M. P., Schwartz, C. & Kornberg, T. B. Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor. Cell 89, 1043–1053 (1997). The first paper to recognize that hedgehog signalling is mediated by preventing the constitutive cleavage of CI, the Drosophila homologue of the mammalian GLI proteins.

    Article  CAS  PubMed  Google Scholar 

  6. Bai, C. B., Stephen, D. & Joyner, A. L. All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev. Cell 6, 103–115 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Echelard, Y. et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75, 1417–1430 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. Chiang, C. et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407–413 (1996). Reports the phenotype of the Shh−/− loss-of-function mutant and directly validates the requirement for SHH in ventral patterning of the nervous system.

    Article  CAS  PubMed  Google Scholar 

  9. Wijgerde, M., McMahon, J. A., Rule, M. & McMahon, A. P. A direct requirement for Hedgehog signaling for normal specification of all ventral progenitor domains in the presumptive mammalian spinal cord. Genes Dev. 16, 2849–2864 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Goodrich, L. V., Milenkovic, L., Higgins, K. M. & Scott, M. P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109–1113 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Marigo, V., Davey, R. A., Zuo, Y., Cunningham, J. M. & Tabin, C. J. Biochemical evidence that patched is the Hedgehog receptor. Nature 384, 176–179 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Stone, D. M. et al. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 384, 129–134 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Taipale, J., Cooper, M. K., Maiti, T. & Beachy, P. A. Patched acts catalytically to suppress the activity of Smoothened. Nature 418, 892–897 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Chen, J. K., Taipale, J., Young, K. E., Maiti, T. & Beachy, P. A. Small molecule modulation of Smoothened activity. Proc. Natl Acad. Sci. USA 99, 14071–14076 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lum, L. & Beachy, P. A. The Hedgehog response network: sensors, switches, and routers. Science 304, 1755–1759 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Varjosalo, M., Li, S. P. & Taipale, J. Divergence of hedgehog signal transduction mechanism between Drosophila and mammals. Dev. Cell 10, 177–186 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Tay, S. Y., Ingham, P. W. & Roy, S. A homologue of the Drosophila kinesin-like protein Costal2 regulates Hedgehog signal transduction in the vertebrate embryo. Development 132, 625–634 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Huangfu, D. et al. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83–87 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Huangfu, D. & Anderson, K. V. Cilia and Hedgehog responsiveness in the mouse. Proc. Natl Acad. Sci. USA 102, 11325–11330 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Eggenschwiler, J. T., Espinoza, E. & Anderson, K. V. Rab23 is an essential negative regulator of the mouse Sonic hedgehog signalling pathway. Nature 412, 194–198 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Liu, A., Wang, B. & Niswander, L. A. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development 132, 3103–3111 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Ferrante, M. I. et al. Oral-facial-digital type I protein is required for primary cilia formation and left–right axis specification. Nature Genet. 38, 112–117 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Corbit, K. C. et al. Vertebrate Smoothened functions at the primary cilium. Nature 437, 1018–1021 (2005). Complements a number of recent findings (references 20 and 21) showing that genes associated with cilia function are required for hedgehog signalling by providing the first direct evidence that components in the canonical hedgehog pathway are sequestered to cilia in a manner correlated with active hedgehog signalling.

    Article  CAS  PubMed  Google Scholar 

  24. Haycraft, C. J. et al. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet. 1, e53 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Whitfield, J. F. The neuronal primary cilium — an extrasynaptic signaling device. Cell. Signal. 16, 763–767 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Roelink, H. et al. Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell 76, 761–775 (1994). The first study to provide compelling evidence that SHH could induce different neuronal cell types based on concentration alone, strongly supporting the idea that SHH acted as a morphogen in the patterning of the ventral nervous system.

    Article  CAS  PubMed  Google Scholar 

  27. Roelink, H. et al. Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis. Cell 81, 445–455 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. Briscoe, J., Chen, Y., Jessell, T. M. & Struhl, G. A hedgehog-insensitive form of patched provides evidence for direct long-range morphogen activity of sonic hedgehog in the neural tube. Mol. Cell 7, 1279–1291 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Hynes, M. et al. The seven-transmembrane receptor smoothened cell-autonomously induces multiple ventral cell types. Nature Neurosci. 3, 41–46 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Chamoun, Z. et al. Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science 293, 2080–2084 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Lee, J. D. et al. An acylatable residue of Hedgehog is differentially required in Drosophila and mouse limb development. Dev. Biol. 233, 122–136 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Ma, Y. et al. Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell 111, 63–75 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Bellaiche, Y., The, I. & Perrimon, N. Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion. Nature 394, 85–88 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Kawakami, A. et al. The zebrafish-secreted matrix protein you/scube2 is implicated in long-range regulation of hedgehog signaling. Curr. Biol. 15, 480–488 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Woods, I. G. & Talbot, W. S. The you gene encodes an EGF-CUB protein essential for Hedgehog signaling in zebrafish. PLoS Biol. 3, e66 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Chuang, P. T. & McMahon, A. P. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397, 617–621 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Tenzen, T. et al. The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev. Cell 10, 647–656 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Yao, S., Lum, L. & Beachy, P. The ihog cell-surface proteins bind Hedgehog and mediate pathway activation. Cell 125, 343–357 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Zhang, W., Kang, J. S., Cole, F., Yi, M. J. & Krauss, R. S. Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev. Cell 10, 657–665 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Lei, Q., Zelman, A. K., Kuang, E., Li, S. & Matise, M. P. Transduction of graded Hedgehog signaling by a combination of Gli2 and Gli3 activator functions in the developing spinal cord. Development 131, 3593–3604 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Park, H. L. et al. Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development 127, 1593–1605 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Persson, M. et al. Dorsal–ventral patterning of the spinal cord requires Gli3 transcriptional repressor activity. Genes Dev. 16, 2865–2878 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Matise, M. P., Epstein, D. J., Park, H. L., Platt, K. A. & Joyner, A. L. Gli2 is required for induction of floor plate and adjacent cells, but not most ventral neurons in the mouse central nervous system. Development 125, 2759–2770 (1998)

    Article  CAS  PubMed  Google Scholar 

  44. Ding, Q. et al. Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice. Development 125, 2533–2543 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Bai, C. B. & Joyner, A. L. Gli1 can rescue the in vivo function of Gli2. Development 128, 5161–5172 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Bai, C. B., Auerbach, W., Lee, J. S., Stephen, D. & Joyner, A. L. Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development 129, 4753–4761 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Pan, Y., Bai, C. B., Joyner, A. L. & Wang, B. Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol. Cell Biol. 26, 3365–3377 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Briscoe, J., Pierani, A., Jessell, T. M. & Ericson, J. A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube. Cell 101, 435–445 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Briscoe, J. et al. Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling. Nature 398, 622–627 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Ericson, J. et al. Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling. Cell 90, 169–180 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Stamataki, D., Ulloa, F., Tsoni, S. V., Mynett, A. & Briscoe, J. A gradient of Gli activity mediates graded Sonic Hedgehog signaling in the neural tube. Genes Dev. 19, 626–641 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Litingtung, Y. & Chiang, C. Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3. Nature Neurosci. 3, 979–985 (2000). Revealed that, rather than being simply an instructive factor, much of SHH's role in establishing ventral pattern in the spinal cord is conducted using its ability to prevent dorsalization of the spinal cord through the removal the GLI repressor GLI3.

    Article  CAS  PubMed  Google Scholar 

  53. Novitch, B. G., Wichterle, H., Jessell, T. M. & Sockanathan, S. A requirement for retinoic acid-mediated transcriptional activation in ventral neural patterning and motor neuron specification. Neuron 40, 81–95 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Jarov, A. et al. A dual role for Sonic hedgehog in regulating adhesion and differentiation of neuroepithelial cells. Dev. Biol. 261, 520–536 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Nery, S., Wichterle, H. & Fishell, G. Sonic hedgehog contributes to oligodendrocyte specification in the mammalian forebrain. Development 128, 527–540 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Shimamura, K., Hartigan, D. J., Martinez, S., Puelles, L. & Rubenstein, J. L. Longitudinal organization of the anterior neural plate and neural tube. Development 121, 3923–3933 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Fuccillo, M., Rallu, M., McMahon, A. P. & Fishell, G. Temporal requirement for hedgehog signaling in ventral telencephalic patterning. Development 131, 5031–5040 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Gunhaga, L., Jessell, T. M. & Edlund, T. Sonic hedgehog signaling at gastrula stages specifies ventral telencephalic cells in the chick embryo. Development 127, 3283–3293 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Machold, R. et al. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 39, 937–950 (2003). Directly demonstrated that the adult stem cell niche requires hedgehog signalling for its maintenance. In complementary fashion, two other papers (references 113 and 114) showed that SHH was mitogenic for cells in the adult stem cell niche.

    Article  CAS  PubMed  Google Scholar 

  60. Xu, Q., Wonders, C. P. & Anderson, S. A. Sonic hedgehog maintains the identity of cortical interneuron progenitors in the ventral telencephalon. Development 132, 4987–4998 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Kohtz, J. D., Baker, D. P., Corte, G. & Fishell, G. Regionalization within the mammalian telencephalon is mediated by changes in responsiveness to Sonic Hedgehog. Development 125, 5079–5089 (1998).

    Article  CAS  PubMed  Google Scholar 

  62. Spoelgen, R. et al. LRP2/megalin is required for patterning of the ventral telencephalon. Development 132, 405–414 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. McCarthy, R. A., Barth, J. L., Chintalapudi, M. R., Knaak, C. & Argraves, W. S. Megalin functions as an endocytic sonic hedgehog receptor. J. Biol. Chem. 277, 25660–25667 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Yoshida, M. et al. Emx1 and Emx2 functions in development of dorsal telencephalon. Development 124, 101–111 (1997).

    Article  CAS  PubMed  Google Scholar 

  65. Rallu, M. et al. Dorsoventral patterning is established in the telencephalon of mutants lacking both Gli3 and Hedgehog signaling. Development 129, 4963–4974 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Storm, E. E. et al. Dose-dependent functions of Fgf8 in regulating telencephalic patterning centers. Development 133, 1831–1844 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Ribes, V., Wang, Z., Dolle, P. & Niederreither, K. Retinaldehyde dehydrogenase 2 (RALDH2)-mediated retinoic acid synthesis regulates early mouse embryonic forebrain development by controlling FGF and sonic hedgehog signaling. Development 133, 351–361 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Gutin, G. et al. FGF signalling generates ventral telencephalic cells independently of SHH. Development 133, 2937–2946 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Schell-Apacik, C. et al. SONIC HEDGEHOG mutations causing human holoprosencephaly impair neural patterning activity. Hum. Genet. 113, 170–177 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Huh, S., Hatini, V., Marcus, R. C., Li, S. C. & Lai, E. Dorsal–ventral patterning defects in the eye of BF-1-deficient mice associated with a restricted loss of shh expression. Dev. Biol. 211, 53–63 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Barth, K. A. & Wilson, S. W. Expression of zebrafish nk2.2 is influenced by sonic hedgehog/vertebrate hedgehog-1 and demarcates a zone of neuronal differentiation in the embryonic forebrain. Development 121, 1755–1768 (1995).

    Article  CAS  PubMed  Google Scholar 

  72. Dakubo, G. D. et al. Retinal ganglion cell-derived sonic hedgehog signaling is required for optic disc and stalk neuroepithelial cell development. Development 130, 2967–2980 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Macdonald, R. et al. Midline signalling is required for Pax gene regulation and patterning of the eyes. Development 121, 3267–3278 (1995).

    Article  CAS  PubMed  Google Scholar 

  74. Kiecker, C. & Lumsden, A. Hedgehog signaling from the ZLI regulates diencephalic regional identity. Nature Neurosci. 7, 1242–1249 (2004). Showed that the expression of SHH in the diencephalon controls anterior–posterior patterning. This is particularly intriguing because, akin to these findings, hedgehog signalling in Drosophila is required for the establishment of posterior segment identity.

    Article  CAS  PubMed  Google Scholar 

  75. Agarwala, S., Aglyamova, G. V., Marma, A. K., Fallon, J. F. & Ragsdale, C. W. Differential susceptibility of midbrain and spinal cord patterning to floor plate defects in the talpid2 mutant. Dev. Biol. 288, 206–220 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Agarwala, S. & Ragsdale, C. W. A role for midbrain arcs in nucleogenesis. Development 129, 5779–5788 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Fedtsova, N. & Turner, E. E. Signals from the ventral midline and isthmus regulate the development of Brn3.0-expressing neurons in the midbrain. Mech. Dev. 105, 129–144 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Ishibashi, M. & McMahon, A. P. A sonic hedgehog-dependent signaling relay regulates growth of diencephalic and mesencephalic primordia in the early mouse embryo. Development 129, 4807–4819 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Ye, W., Shimamura, K., Rubenstein, J. L., Hynes, M. A. & Rosenthal, A. FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell 93, 755–766 (1998).

    Article  CAS  PubMed  Google Scholar 

  80. Blaess, S., Corrales, J. D. & Joyner, A. L. Sonic hedgehog regulates Gli activator and repressor functions with spatial and temporal precision in the mid/hindbrain region. Development 133, 1799–1809 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Corrales, J. D., Rocco, G. L., Blaess, S., Guo, Q. & Joyner, A. L. Spatial pattern of sonic hedgehog signaling through Gli genes during cerebellum development. Development 131, 5581–5590 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Dahmane, N. & Ruiz-i-Altaba, A. Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126, 3089–3100 (1999).

    Article  PubMed  Google Scholar 

  83. Lewis, P. M., Gritli-Linde, A., Smeyne, R., Kottmann, A. & McMahon, A. P. Sonic hedgehog signaling is required for expansion of granule neuron precursors and patterning of the mouse cerebellum. Dev. Biol. 270, 393–410 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Wallace, V. A. Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr. Biol. 9, 445–448 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Wechsler-Reya, R. J. & Scott, M. P. Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 22, 103–114 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Corrales, J. D., Blaess, S., Mahoney, E. M. & Joyner, A. L. The level of sonic hedgehog signaling regulates the complexity of cerebellar foliation. Development 133, 1811–1821 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Orentas, D. M., Hayes, J. E., Dyer, K. L. & Miller, R. H. Sonic hedgehog signaling is required during the appearance of spinal cord oligodendrocyte precursors. Development 126, 2419–2429 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Pringle, N. P. et al. Determination of neuroepithelial cell fate: induction of the oligodendrocyte lineage by ventral midline cells and sonic hedgehog. Dev. Biol. 177, 30–42 (1996).

    Article  CAS  PubMed  Google Scholar 

  89. Poncet, C. 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. 60, 13–32 (1996). The first study, along with references 87 and 88, to show that SHH signalling could directly mediate the generation of oligodendrocytes in the spinal cord.

    Article  CAS  PubMed  Google Scholar 

  90. Lu, Q. R. et al. Sonic hedgehog-regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. Neuron 25, 317–329 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Zhou, Q., Wang, S. & Anderson, D. J. Identification of a novel family of oligodendrocyte lineage-specific basic helix-loop-helix transcription factors. Neuron 25, 331–343 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Lu, Q. R. et al. Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell 109, 75–86 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Zhou, Q. & Anderson, D. J. The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell 109, 61–73 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Tekki-Kessaris, N. et al. Hedgehog-dependent oligodendrocyte lineage specification in the telencephalon. Development 128, 2545–2554 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Kessaris, N., Jamen, F., Rubin, L. L. & Richardson, W. D. Cooperation between sonic hedgehog and fibroblast growth factor/MAPK signalling pathways in neocortical precursors. Development 131, 1289–1298 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Gabay, L., Lowell, S., Rubin, L. L. & Anderson, D. J. Deregulation of dorsoventral patterning by FGF confers trilineage differentiation capacity on CNS stem cells in vitro. Neuron 40, 485–499 (2003).

    Article  CAS  PubMed  Google Scholar 

  97. Lee, J., Platt, K. A., Censullo, P. & Ruiz i Altaba, A. Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. Development 124, 2537–2552 (1997).

    Article  CAS  PubMed  Google Scholar 

  98. Liu, A., Joyner, A. L. & Turnbull, D. H. Alteration of limb and brain patterning in early mouse embryos by ultrasound-guided injection of Shh-expressing cells. Mech. Dev. 75, 107–115 (1998).

    Article  CAS  PubMed  Google Scholar 

  99. Rowitch, D. H. et al. Sonic hedgehog regulates proliferation and inhibits differentiation of CNS precursor cells. J. Neurosci. 19, 8954–8965 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kenney, A. M., Cole, M. D. & Rowitch, D. H. Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development 130, 15–28 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Kenney, A. M. & Rowitch, D. H. Sonic hedgehog promotes G1 cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol. Cell Biol. 20, 9055–9067 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Oliver, T. G. et al. Transcriptional profiling of the Sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors. Proc. Natl Acad. Sci. USA 100, 7331–7336 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kenney, A. M., Widlund, H. R. & Rowitch, D. H. Hedgehog and PI-3 kinase signaling converge on Nmyc1 to promote cell cycle progression in cerebellar neuronal precursors. Development 131, 217–228 (2004).

    Article  CAS  PubMed  Google Scholar 

  104. Sjostrom, S. K., Finn, G., Hahn, W. C., Rowitch, D. H. & Kenney, A. M. The Cdk1 complex plays a prime role in regulating N-myc phosphorylation and turnover in neural precursors. Dev. Cell 9, 327–338 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Thibert, C. et al. Inhibition of neuroepithelial patched-induced apoptosis by sonic hedgehog. Science 301, 843–846 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Culverwell, J. & Karlstrom, R. O. Making the connection: retinal axon guidance in the zebrafish. Semin. Cell Dev. Biol. 13, 497–506 (2002).

    Article  PubMed  Google Scholar 

  107. Trousse, F., Marti, E., Gruss, P., Torres, M. & Bovolenta, P. Control of retinal ganglion cell axon growth: a new role for Sonic hedgehog. Development 128, 3927–3936 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Strahle, U., Fischer, N. & Blader, P. Expression and regulation of a netrin homologue in the zebrafish embryo. Mech. Dev. 62, 147–160 (1997).

    Article  CAS  PubMed  Google Scholar 

  109. Barresi, M. J., Hutson, L. D., Chien, C. B. & Karlstrom, R. O. Hedgehog regulated Slit expression determines commissure and glial cell position in the zebrafish forebrain. Development 132, 3643–3656 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Charron, F., Stein, E., Jeong, J., McMahon, A. P. & Tessier-Lavigne, M. The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance. Cell 113, 11–23 (2003). Provides compelling genetic evidence that hedgehog signalling mediates axonal pathfinding across the ventral midline. This was the first study to show that SHH has a role as a chemoattractant.

    Article  CAS  PubMed  Google Scholar 

  111. Bourikas, D. et al. Sonic hedgehog guides commissural axons along the longitudinal axis of the spinal cord. Nature Neurosci. 8, 297–304 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716 (1999).

    Article  CAS  PubMed  Google Scholar 

  113. Lai, K., Kaspar, B. K., Gage, F. H. & Schaffer, D. V. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nature Neurosci. 6, 21–27 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Palma, V. et al. Sonic hedgehog controls stem cell behavior in the postnatal and adult brain. Development 132, 335–344 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Joyner, A. L. & Zervas, M. Genetic inducible fate mapping in mouse: establishing genetic lineages and defining genetic neuroanatomy in the nervous system. Dev. Dyn. 235, 2376–2385 (2006).

    Article  PubMed  Google Scholar 

  116. Ahn, S. & Joyner, A. L. In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature 437, 894–897 (2005). Used genetic fate mapping of the hedgehog reporter gene Gli1 to demonstrate that adult neural stem cells respond directly to hedgehog signalling.

    Article  CAS  PubMed  Google Scholar 

  117. Palma, V. & Ruiz i Altaba, A. Hedgehog-GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex. Development 131, 337–345 (2004).

    Article  CAS  PubMed  Google Scholar 

  118. Solecki, D. J., Liu, X. L., Tomoda, T., Fang, Y. & Hatten, M. E. Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation. Neuron 31, 557–568 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Horabin, J. I. Splitting the Hedgehog signal: sex and patterning in Drosophila. Development 132, 4801–4810 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Chen, Y. & Struhl, G. Dual roles for patched in sequestering and transducing Hedgehog. Cell 87, 553–563 (1996).

    Article  CAS  PubMed  Google Scholar 

  121. Lu, Q. R., Cai, L., Rowitch, D., Cepko, C. L. & Stiles, C. D. Ectopic expression of Olig1 promotes oligodendrocyte formation and reduces neuronal survival in developing mouse cortex. Nature Neurosci. 4, 973–974 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Sandra Blaess and Alex Schier for their critical reading of this review and their many helpful comments. We would also like to thank the Joyner and Fishell laboratories. A.J. and G.F. are supported by grants from the National Institutes of Health, USA.

Author information

Authors and Affiliations

  1. Developmental Genetics Program and the Department of Cell Biology, Skirball Institute of Biomolecular Medicine, New York University Medical Center, 540 First Avenue, New York, 10016, NY, USA

    Marc Fuccillo, Alexandra L. Joyner & Gord Fishell

Authors
  1. Marc Fuccillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexandra L. Joyner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gord Fishell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gord Fishell.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

Bardet-Biedl syndrome

Gorlin's syndrome

FURTHER INFORMATION

Fishell's laboratory

Joyner's laboratory

Glossary

Morphogen

A secreted factor that can induce more than two different cell fates over a sheet of cells in a concentration-dependent manner by forming a gradient.

Mitogen

Any factor that promotes proliferation.

V0–V3 interneuron domains

Subdomains of the ventral spinal cord that give rise to specific populations of interneurons.

Homotopic cell sorting

The sorting of populations of cells that possess similar adhesion properties.

Medial ganglionic eminence

(MGE). A transient proliferative zone in the ventral telencephalon that is both patterned by and ultimately expresses sonic hedgehog. It seems to be the origin of most cortical interneurons, as well as a subpopulation of oligodendrocytes.

Zona limitans intrathalamica

(ZLI). An embryonic structure that is positioned at the boundary between the dorsal and ventral thalamus and acts as an organizing centre, at least partially due to its expression of SHH.

Adult proliferative niche

Select regions within the telencephalon in which postnatal neurogenesis occurs.

Alar plate

The dorsal aspect of the developing neural plate/tube.

Bergmann glia

A specialized form of radial glia found in the cerebellum that, unlike most radial glia, persists throughout life.

Foliation

The process by which neural tissue is folded into gyri and sulci. This occurs most prominently in the cerebellum of mice and in the cerebral cortex of higher vertebrates, such as ferrets, monkeys and humans.

Hyperplasia

Exuberant proliferation that might or might not be cancerous in nature.

Morpholinos

A modified form of RNA that interferes with translation of the complementary RNA.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fuccillo, M., Joyner, A. & Fishell, G. Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development. Nat Rev Neurosci 7, 772–783 (2006). https://doi.org/10.1038/nrn1990

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1990

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing