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  • Review Article
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Mechanisms of ventral patterning in the vertebrate nervous system

Nature Reviews Neuroscience volume 7, pages 103–114 (2006)Cite this article

Key Points

  • Hedgehog (HH) signals are necessary and sufficient to specify ventral fates in the spinal cord, telencephalon and eye. At least in the spinal cord, these signals act as morphogens — long-range diffusible factors that specify distinct fates at different concentrations.

  • Most ventral fates in the neural tube are recovered in the absence of both HH signalling and GLI3 (GLI-Kruppel family member 3)-repressor activity. This shows that a major role of HH signalling is to inhibit GLI3 from being processed into its repressive form.

  • In the spinal cord, HH signalling is required for the specification of floor plate and V3 interneurons, and for the correct spatial organization of MNs, and V1 and V0 interneurons, even in the absence of GLI3-repressor activity.

  • Bone morphogenetic proteins (BMPs) are expressed in the dorsal neural tube and BMP antagonists are expressed in close proximity to the ventral neural tube. This creates a dorsal (high) to ventral (low) concentration gradient of BMP signalling, which specifies distinct dorsal fates and might also influence the specification of more ventral fates.

  • Retinoic acid (RA) can specify intermediate domains in the spinal cord, eye and telencephalon. High levels of RA also seem to repress the most ventral fates in all three of these structures.

  • Fibroblast growth factor (FGF) signals are sufficient to induce ventral fates in the eye and telencephalon. In the telencephalon, FGF signals also delay differentiation, but in the eye they promote differentiation. In the developing spinal cord, FGF signals initially inhibit neuronal differentiation, but at later stages FGF signals can act in concert with HH and RA signals to specify different ventral fates.

  • The interaction of FGF signalling with HH and RA signalling is context dependent and includes collaborating with HH signals, antagonizing HH signals, acting independently of HH signals, collaborating with RA and antagonizing RA.

Abstract

Dorsoventral patterning of the neural tube has a crucial role in shaping the functional organization of the CNS. It is well established that hedgehog signalling plays a key role in specifying ventral cell types throughout the neuroectoderm, and major progress has been made in elucidating how hedgehog signalling works in this ventral specification. In addition, other molecular pathways, including nodal, retinoic acid and fibroblast growth factor signalling, have been identified as important molecular cues for ventral patterning of the spinal cord, telencephalon and eye. Here, we discuss recent advances in this field, highlighting the emerging interplay of these signalling pathways in the molecular specification of ventral patterning at different rostrocaudal levels of the CNS.

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Figure 1: Dorsoventral patterning in the vertebrate CNS.
Figure 2: Ventral patterning in the spinal cord, telencephalon and eye.
Figure 3: Ventral patterning of spinal cord and telencephalon in the absence of both hedgehog signalling and GLI3 repressor activity.
Figure 4: Retinoic acid signalling is required for the specification of intermediate dorsoventral domains in the spinal cord and telencephalon.
Figure 5: A basic molecular network controls ventral patterning of the CNS.

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References

  1. Sanes, D. H., Reh, T. A. & Harris, W. A. Development of the Nervous System (Elsevier Academic, USA, 2006).

    Google Scholar 

  2. Lumsden, A. & Krumlauf, R. Patterning the vertebrate neuraxis. Science 274, 1109–1115 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Rubenstein, J. L., Shimamura, K., Martinez, S. & Puelles, L. Regionalization of the prosencephalic neural plate. Annu. Rev. Neurosci. 21, 445–477 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. 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). This seminal paper describes how SHH signalling specifies different DV progenitor domains in the ventral spinal cord. The authors also show that each of these progenitor domains expresses a unique combination of transcription factors and generates a distinct class of postmitotic neuron.

    Article  CAS  PubMed  Google Scholar 

  5. Shirasaki, R. & Pfaff, S. L. Transcriptional codes and the control of neuronal identity. Annu. Rev. Neurosci. 25, 251–281 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Tabata, T. & Takei, Y. Morphogens, their identification and regulation. Development 131, 703–712 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Wilson, S. W. & Houart, C. Early steps in the development of the forebrain. Dev. Cell 6, 167–181 (2004). A great introduction to the patterning of the forebrain and the signalling pathways involved.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Briscoe, J. & Ericson, J. Specification of neuronal fates in the ventral neural tube. Curr. Opin. Neurobiol. 11, 43–49 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. Ruiz i Altaba, A., Nguyen, V. & Palma, V. The emergent design of the neural tube: prepattern, SHH morphogen and GLI code. Curr. Opin. Genet. Dev. 13, 513–521 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Briscoe, J. & Ericson, J. The specification of neuronal identity by graded sonic hedgehog signalling. Semin. Cell Dev. Biol. 10, 353–362 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Litingtung, Y. & Chiang, C. Control of Shh activity and signaling in the neural tube. Dev. Dyn. 219, 143–154 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Wilson, L. & Maden, M. The mechanisms of dorsoventral patterning in the vertebrate neural tube. Dev. Biol. 282, 1–13 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Chiang, C. et al. Cyclopia and defective axial patterning in mice lacking sonic hedgehog gene function. Nature 383, 407–413 (1996). Describes the phenotype of mouse embryos that lack SHH. These results provide genetic evidence of the requirement for SHH signalling in the specification of most ventral CNS fates.

    Article  CAS  PubMed  Google Scholar 

  15. 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). Demonstrates that HH signalling is required directly in ventral cells for the specification of all ventral spinal cord fates, with the possible exception of some V0 cells. Along with references 34 and 36, this provides conclusive evidence that SHH acts as a morphogen in the ventral spinal cord.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rallu, M., Corbin, J. G. & Fishell, G. Parsing the prosencephalon. Nature Rev. Neurosci. 3, 943–951 (2002).

    Article  CAS  Google Scholar 

  17. Mathieu, J., Barth, A., Rosa, F. M., Wilson, S. W. & Peyrieras, N. Distinct and cooperative roles for nodal and hedgehog signals during hypothalamic development. Development 129, 3055–3065 (2002).

    CAS  PubMed  Google Scholar 

  18. Rohr, K. B., Barth, K. A., Varga, Z. M. & Wilson, S. W. The nodal pathway acts upstream of hedgehog signaling to specify ventral telencephalic identity. Neuron 29, 341–351 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    CAS  PubMed  Google Scholar 

  20. 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).

    CAS  PubMed  Google Scholar 

  21. Rallu, M. et al. Dorsoventral patterning is established in the telencephalon of mutants lacking both Gli3 and hedgehog signaling. Development 129, 4963–4974 (2002). References 21 and 22 show that ventral telencephalic patterning requires HH signalling, but appears normal when GLI3 is also knocked out.

    CAS  PubMed  Google Scholar 

  22. 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 

  23. Peters, M. A. Patterning the neural retina. Curr. Opin. Neurobiol. 12, 43–48 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. McLaughlin, T., Hindges, R. & O'Leary, D. D. Regulation of axial patterning of the retina and its topographic mapping in the brain. Curr. Opin. Neurobiol. 13, 57–69 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Lupo, G. et al. Homeobox genes in the genetic control of eye development. Int. J. Dev. Biol. 44, 627–636 (2000).

    CAS  PubMed  Google Scholar 

  26. Lupo, G. et al. Dorsoventral patterning of the Xenopus eye: a collaboration of retinoid, hedgehog and FGF receptor signaling. Development 132, 1737–1748 (2005). Results suggest that the ventral regionalization of the eye is specified by interactions among HH, RA and FGF.

    Article  CAS  PubMed  Google Scholar 

  27. Peters, M. A. & Cepko, C. L. The dorsal–ventral axis of the neural retina is divided into multiple domains of restricted gene expression which exhibit features of lineage compartments. Dev. Biol. 251, 59–73 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Russell, C. The roles of hedgehogs and fibroblast growth factors in eye development and retinal cell rescue. Vision Res. 43, 899–912 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Yang, X. J. Roles of cell-extrinsic growth factors in vertebrate eye pattern formation and retinogenesis. Semin. Cell Dev. Biol. 15, 91–103 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sasagawa, S., Takabatake, T., Takabatake, Y., Muramatsu, T. & Takeshima, K. Axes establishment during eye morphogenesis in Xenopus by coordinate and antagonistic actions of BMP4, Shh, and RA. Genesis 33, 86–96 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Take-uchi, M., Clarke, J. D. & Wilson, S. W. Hedgehog signalling maintains the optic stalk–retinal interface through the regulation of Vax gene activity. Development 130, 955–968 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Yamamoto, Y., Stock, D. W. & Jeffery, W. R. Hedgehog signalling controls eye degeneration in blind cavefish. Nature 431, 844–847 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Tian, N. M. & Price, D. J. Why cavefish are blind. Bioessays 27, 235–238 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. 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 

  35. 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). Shows that different levels of GLI transcription factor activity are sufficient to cell-autonomously induce all of the different ventral fates in the spinal cord.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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). These authors overexpress a constitutively active form of PTC, which represses HH signalling. They show that this constitutively active PTC cell-autonomously inhibits V3–V0 and MN fates within their normal domains and induces ectopic V2, V1 and V0 neurons in the ventral spinal cord. Along with references 14 and 34, this provides conclusive evidence that SHH acts as a morphogen in the ventral spinal cord. This paper also shows that there is a feedback mechanism in the spinal cord, whereby SHH signalling normally acts to limit the range of direct SHH action.

    Article  CAS  PubMed  Google Scholar 

  37. Ericson, J., Morton, S., Kawakami, A., Roelink, H. & Jessell, T. M. Two critical periods of sonic hedgehog signaling required for the specification of motor neuron identity. Cell 87, 661–673 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Poh, A. et al. Patterning of the vertebrate ventral spinal cord. Int. J. Dev. Biol. 46, 597–608 (2002).

    CAS  PubMed  Google Scholar 

  39. Park, H. C., Shin, J. & Appel, B. Spatial and temporal regulation of ventral spinal cord precursor specification by hedgehog signaling. Development 131, 5959–5969 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. 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).

    Article  CAS  PubMed  Google Scholar 

  41. 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 

  42. Koebernick, K. & Pieler, T. Gli-type zinc finger proteins as bipotential transducers of hedgehog signaling. Differentiation 70, 69–76 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Jacob, J. & Briscoe, J. Gli proteins and the control of spinal-cord patterning. EMBO Rep. 4, 761–765 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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 

  45. 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 

  46. Tyurina, O. V. et al. Zebrafish Gli3 functions as both an activator and a repressor in hedgehog signaling. Dev. Biol. 277, 537–556 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Chizhikov, V. V. & Millen, K. J. Roof plate-dependent patterning of the vertebrate dorsal central nervous system. Dev. Biol. 277, 287–295 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Timmer, J. R., Wang, C. & Niswander, L. BMP signaling patterns the dorsal and intermediate neural tube via regulation of homeobox and helix–loop–helix transcription factors. Development 129, 2459–2472 (2002).

    CAS  PubMed  Google Scholar 

  49. Chesnutt, C., Burrus, L. W., Brown, A. M. & Niswander, L. Coordinate regulation of neural tube patterning and proliferation by TGFβ and WNT activity. Dev. Biol. 274, 334–347 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Wine-Lee, L. et al. Signaling through BMP type 1 receptors is required for development of interneuron cell types in the dorsal spinal cord. Development 131, 5393–5403 (2004). These authors used a combination of a mouse knockout of BMP receptor BMPR1B and a conditional knockout that only eliminates BMP receptor BMPR1A in the neural tube to show that BMP signalling is directly required for the specification of D1 and D2 dorsal interneuron fates. However, more ventral fates are not affected in these double-mutant embryos.

    Article  CAS  PubMed  Google Scholar 

  51. McMahon, J. A. et al. Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. Genes Dev. 12, 1438–1452 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liem, K. F. Jr, Jessell, T. M. & Briscoe, J. Regulation of the neural patterning activity of sonic hedgehog by secreted BMP inhibitors expressed by notochord and somites. Development 127, 4855–4866 (2000).

    CAS  PubMed  Google Scholar 

  53. Patten, I. & Placzek, M. Opponent activities of Shh and BMP signaling during floor plate induction in vivo. Curr. Biol. 12, 47–52 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Barth, K. A. et al. Bmp activity establishes a gradient of positional information throughout the entire neural plate. Development 126, 4977–4987 (1999).

    CAS  PubMed  Google Scholar 

  55. Nguyen, V. H. et al. Dorsal and intermediate neuronal cell types of the spinal cord are established by a BMP signaling pathway. Development 127, 1209–1220 (2000).

    CAS  PubMed  Google Scholar 

  56. Meyer, N. P. & Roelink, H. The amino-terminal region of Gli3 antagonizes the Shh response and acts in dorsoventral fate specification in the developing spinal cord. Dev. Biol. 257, 343–355 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Furuta, Y., Piston, D. W. & Hogan, B. L. Bone morphogenetic proteins (BMPs) as regulators of dorsal forebrain development. Development 124, 2203–2212 (1997).

    CAS  PubMed  Google Scholar 

  58. Hebert, J. M., Mishina, Y. & McConnell, S. K. BMP signaling is required locally to pattern the dorsal telencephalic midline. Neuron 35, 1029–1041 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Anderson, R. M., Lawrence, A. R., Stottmann, R. W., Bachiller, D. & Klingensmith, J. Chordin and noggin promote organizing centers of forebrain development in the mouse. Development 129, 4975–4987 (2002).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  61. Houart, C. et al. Establishment of the telencephalon during gastrulation by local antagonism of Wnt signaling. Neuron 35, 255–265 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Lupo, G., Harris, W. A., Barsacchi, G. & Vignali, R. Induction and patterning of the telencephalon in Xenopus laevis. Development 129, 5421–5436 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Sakuta, H. et al. Ventroptin: a BMP-4 antagonist expressed in a double-gradient pattern in the retina. Science 293, 111–115 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Adler, R. & Belecky-Adams, T. L. The role of bone morphogenetic proteins in the differentiation of the ventral optic cup. Development 129, 3161–3171 (2002).

    CAS  PubMed  Google Scholar 

  65. Koshiba-Takeuchi, K. et al. Tbx5 and the retinotectum projection. Science 287, 134–137 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Murali, D. et al. Distinct developmental programs require different levels of Bmp signaling during mouse retinal development. Development 132, 913–923 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Takabatake, Y., Takabatake, T., Sasagawa, S. & Takeshima, K. Conserved expression control and shared activity between cognate T-box genes Tbx2 and Tbx3 in connection with Sonic hedgehog signaling during Xenopus eye development. Dev. Growth Differ. 44, 257–271 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Zhang, X. M. & Yang, X. J. Temporal and spatial effects of sonic hedgehog signaling in chick eye morphogenesis. Dev. Biol. 233, 271–290 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Golz, S., Lantin, C. & Mey, J. Retinoic acid-dependent regulation of BMP4 and Tbx5 in the embryonic chick retina. Neuroreport 15, 2751–2755 (2004).

    CAS  PubMed  Google Scholar 

  70. Weston, C. R. et al. JNK initiates a cytokine cascade that causes Pax2 expression and closure of the optic fissure. Genes Dev. 17, 1271–1280 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Conlon, F. L. et al. A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development 120, 1919–1928 (1994).

    CAS  PubMed  Google Scholar 

  72. Feldman, B. et al. Zebrafish organizer development and germ-layer formation require nodal-related signals. Nature 395, 181–185 (1998).

    Article  CAS  PubMed  Google Scholar 

  73. Rebagliati, M. R., Toyama, R., Haffter, P. & Dawid, I. B. cyclops encodes a nodal-related factor involved in midline signaling. Proc. Natl Acad. Sci. USA 95, 9932–9937 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Sampath, K. et al. Induction of the zebrafish ventral brain and floorplate requires cyclops/nodal signalling. Nature 395, 185–189 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Hatta, K., Kimmel, C. B., Ho, R. K. & Walker, C. The cyclops mutation blocks specification of the floor plate of the zebrafish central nervous system. Nature 350, 339–341 (1991).

    Article  CAS  PubMed  Google Scholar 

  76. Hatta, K., Puschel, A. W. & Kimmel, C. B. Midline signaling in the primordium of the zebrafish anterior central nervous system. Proc. Natl Acad. Sci. USA 91, 2061–2065 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Brand, M. et al. Mutations affecting development of the midline and general body shape during zebrafish embryogenesis. Development 123, 129–142 (1996).

    CAS  PubMed  Google Scholar 

  78. Gritsman, K. et al. The EGF-CFC protein one-eyed pinhead is essential for nodal signaling. Cell 97, 121–132 (1999).

    Article  CAS  PubMed  Google Scholar 

  79. Hammerschmidt, M. et al. Mutations affecting morphogenesis during gastrulation and tail formation in the zebrafish, Danio rerio. Development 123, 143–151 (1996).

    CAS  PubMed  Google Scholar 

  80. Pogoda, H. M., Solnica-Krezel, L., Driever, W. & Meyer, D. The zebrafish forkhead transcription factor FoxH1/Fast1 is a modulator of nodal signaling required for organizer formation. Curr. Biol. 10, 1041–1049 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Sirotkin, H. I., Gates, M. A., Kelly, P. D., Schier, A. F. & Talbot, W. S. Fast1 is required for the development of dorsal axial structures in zebrafish. Curr. Biol. 10, 1051–1054 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Strähle, U. et al. one-eyed pinhead is required for development of the ventral midline of the zebrafish (Danio rerio) neural tube. Genes Funct. 1, 131–148 (1997).

    Article  PubMed  Google Scholar 

  83. Müller, F. et al. Direct action of the nodal-related signal cyclops in induction of sonic hedgehog in the ventral midline of the CNS. Development 127, 3889–3897 (2000).

    PubMed  Google Scholar 

  84. Placzek, M. & Briscoe, J. The floor plate: multiple cells, multiple signals. Nature Rev. Neurosci. 6, 230–240 (2005).

    Article  CAS  Google Scholar 

  85. Strähle, U., Lam, C. S., Ertzer, R. & Rastegar, S. Vertebrate floor-plate specification: variations on common themes. Trends Genet. 20, 155–162 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Etheridge, L. A., Wu, T., Liang, J. O., Ekker, S. C. & Halpern, M. E. Floor plate develops upon depletion of tiggy-winkle and sonic hedgehog. Genesis 30, 164–169 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Lewis, K. E. & Eisen, J. S. Hedgehog signaling is required for primary motoneuron induction in zebrafish. Development 128, 3485–3495 (2001).

    CAS  PubMed  Google Scholar 

  88. Patten, I., Kulesa, P., Shen, M. M., Fraser, S. & Placzek, M. Distinct modes of floor plate induction in the chick embryo. Development 130, 4809–4821 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Pierani, A., Brenner-Morton, S., Chiang, C. & Jessell, T. M. A sonic hedgehog-independent, retinoid-activated pathway of neurogenesis in the ventral spinal cord. Cell 97, 903–915 (1999).

    Article  CAS  PubMed  Google Scholar 

  90. Wilson, L., Gale, E., Chambers, D. & Maden, M. Retinoic acid and the control of dorsoventral patterning in the avian spinal cord. Dev. Biol. 269, 433–446 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Marklund, M. et al. Retinoic acid signalling specifies intermediate character in the developing telencephalon. Development 131, 4323–4332 (2004). Provides evidence for a role of RA in LGE specification and FGF in MGE specification.

    Article  CAS  PubMed  Google Scholar 

  92. Li, H. et al. A retinoic acid synthesizing enzyme in ventral retina and telencephalon of the embryonic mouse. Mech. Dev. 95, 283–289 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Suzuki, R. et al. Identification of RALDH-3, a novel retinaldehyde dehydrogenase, expressed in the ventral region of the retina. Mech. Dev. 98, 37–50 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Dupe, V. et al. A newborn lethal defect due to inactivation of retinaldehyde dehydrogenase type 3 is prevented by maternal retinoic acid treatment. Proc. Natl Acad. Sci. USA 100, 14036–14041 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Matt, N. et al. Retinoic acid-dependent eye morphogenesis is orchestrated by neural crest cells. Development 132, 4789–4800 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Sen, J., Harpavat, S., Peters, M. A. & Cepko, C. L. Retinoic acid regulates the expression of dorsoventral topographic guidance molecules in the chick retina. Development 132, 5147–5159 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. 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 

  98. Diez del Corral, R. et al. Opposing FGF and retinoid pathways control ventral neural pattern, neuronal differentiation, and segmentation during body axis extension. Neuron 40, 65–79 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Shinya, M., Koshida, S., Sawada, A., Kuroiwa, A. & Takeda, H. Fgf signalling through MAPK cascade is required for development of the subpallial telencephalon in zebrafish embryos. Development 128, 4153–4164 (2001).

    CAS  PubMed  Google Scholar 

  100. Walshe, J. & Mason, I. Unique and combinatorial functions of Fgf3 and Fgf8 during zebrafish forebrain development. Development 130, 4337–4349 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Sun, X., Meyers, E. N., Lewandoski, M. & Martin, G. R. Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes Dev. 13, 1834–1846 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kuschel, S., Ruther, U. & Theil, T. A disrupted balance between Bmp/Wnt and Fgf signaling underlies the ventralization of the Gli3 mutant telencephalon. Dev. Biol. 260, 484–495 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Carl, M. & Wittbrodt, J. Graded interference with FGF signalling reveals its dorsoventral asymmetry at the mid–hindbrain boundary. Development 126, 5659–5667 (1999).

    CAS  PubMed  Google Scholar 

  104. Martinez-Morales, J. R. et al. Differentiation of the vertebrate retina is coordinated by an FGF signaling center. Dev. Cell 8, 565–574 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Diez del Corral, R. & Storey, K. G. Opposing FGF and retinoid pathways: a signalling switch that controls differentiation and patterning onset in the extending vertebrate body axis. Bioessays 26, 857–869 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Zhang, X. M., Lin, E. & Yang, X. J. Sonic hedgehog-mediated ventralization disrupts formation of the midbrain–hindbrain junction in the chick embryo. Dev. Neurosci. 22, 207–216 (2000).

    Article  CAS  PubMed  Google Scholar 

  107. Corbo, J. C., Erives, A., Di Gregorio, A., Chang, A. & Levine, M. Dorsoventral patterning of the vertebrate neural tube is conserved in a protochordate. Development 124, 2335–2344 (1997).

    CAS  PubMed  Google Scholar 

  108. Hudson, C. & Yasuo, H. Patterning across the ascidian neural plate by lateral Nodal signalling sources. Development 132, 1199–1210 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Katsuyama, Y. et al. Early specification of ascidian larval motor neurons. Dev. Biol. 278, 310–322 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Wichterle, H., Lieberam, I., Porter, J. A. & Jessell, T. M. Directed differentiation of embryonic stem cells into motor neurons. Cell 110, 385–397 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Watanabe, K. et al. Directed differentiation of telencephalic precursors from embryonic stem cells. Nature Neurosci. 8, 288–296 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  113. Furimsky, M. & Wallace, V. A. Complementary Gli activity mediates early patterning of the mouse visual system. Dev. Dyn. 8 Dec 2005 [epub ahead of print].

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Acknowledgements

We thank the referees for helpful comments on earlier drafts of this manuscript and we apologise to any of our colleagues whose work we have failed to cite due to space limitations. Work in K.E.L.'s laboratory is funded by the Royal Society, London, UK, and Cambridge University Isaac Newton Trust, UK; work in W.A.H.'s laboratory is funded by the Wellcome Trust, London, UK.

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Authors and Affiliations

  1. Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3DY, UK

    Giuseppe Lupo, William A. Harris & Katharine E. Lewis

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  1. Giuseppe Lupo
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  2. William A. Harris
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  3. Katharine E. Lewis
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Corresponding author

Correspondence to William A. Harris.

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DATABASES

ZFIN

cyc

Fgf3

Fgf8

oep

smo

FURTHER INFORMATION

Harris's laboratory

Lewis's laboratory

Glossary

Retinoic acid

(RA). A product of vitamin A metabolism. RA is a small molecule that controls gene expression by binding to retinoic acid receptors in cells.

Floor plate

A specialized population of cells at the most ventral part (floor) of the neural tube.

Notochord

A derivative of the most dorsal mesoderm, consisting of a rod of cells that extends beneath the ventral neural tube along the AP axis of most of the embryo.

Neuroectoderm

The dorsal part of the ectoderm germ layer, which gives rise to the neural tissue.

Somitic mesoderm

Located laterally to the notochord, this mesodermal tissue is subdivided into segmental units (somites), which give rise to skeletal muscle and bones.

Gnathostome

A comprehensive division of vertebrates, including all that have distinct jaws, in contrast to the leptocardians and marsipobranchs (cyclostomes), which lack them.

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Lupo, G., Harris, W. & Lewis, K. Mechanisms of ventral patterning in the vertebrate nervous system. Nat Rev Neurosci 7, 103–114 (2006). https://doi.org/10.1038/nrn1843

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