Mechanisms of ventral patterning in the vertebrate nervous system

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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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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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Correspondence to William A. Harris.

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DATABASES

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FURTHER INFORMATION

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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) doi:10.1038/nrn1843

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