Sonic hedgehog in Hypothalamus Development

Abstract

Sonic hedgehog (SHH) is a secreted signaling protein able to confer ventral cell fate to the spinal cord on the basis of a concentration gradient that translates into activation of specific genes through Gli transcription factors. The intricate and dynamic expression pattern of Shh in the forebrain raises the question of its function in the developing hypothalamus. Experiments in chick and mouse show that SHH from the prechordal plate cooperates with Bone Morphogenetic Proteins (BMPs) to induce a special “hypothalamic floor plate” where Shh expression will be activated by three transcription factors, Nkx2-1, Six3, and Sox2/3. Conditional mouse mutants show that this new source of SHH is responsible for hypothalamic growth as well as full differentiation of most hypothalamic cell types and the formation of the lateral hypothalamus. Experiments on chick embryos indicate that for the specification of hypothalamic regions Shh cooperates with Fgf10. For the final differentiation of the basal hypothalamic regions and hypophysis, repression of Shh by T-box proteins is necessary. Precisely how SHH unlocks hypothalamic cell fates is not entirely clear. But in mouse and zebrafish, Shh bestows neuroendocrine cell fates through a complex relation with Rax/rx3.

Key References

• Alvarez-Bolado et al. (2012)—Fate-mapping shows that the Shh-expressing domains of the presumptive hypothalamus generate the tuberal and mammillary regions (but not the preoptic and anterior regions).

• Chiang et al. (1996)—Inactivation of Shh in transgenic mice confirmed that Shh is required for the formation of ventral structures (including the entire hypothalamus) in the central nervous system.

• Dale et al. (1997)—Experiments on chick embryos show that the hypothalamic floor plate is specified by the prechordal mesoderm.

• Geng et al. (2008)—A network of essential regulators controls the partition of the telencephalon into left and right hemispheres. As a consequence, in certain genetic backgrounds, neural Shh is required for this process to be successful.

• Haddad-Tóvolli et al. (2015)—Analysis of mouse mutant phenotypes shows how different combinations of Gli transcription factors, acting downstream Shh signalling, are involved in the specification of the four classical hypothalamic regions.

• Manning L et al. (2006)—The mechanism behind the impressive change in the pattern of Shh expression in the hypothalamus, and its role, explained.

• Szabó et al. (2009)—Thirteen years after the full Shh null mutant (Chiang et al. 1996), the role of neural Shh vs prechordal Shh in hypothalamic development were dissected by using conditional mouse mutants.

• Shimogori et al. (2010)—A second conditional mutant analyzing the role of Shh from different sources (neural or prechordal) on the developing hypothalamus.

• Zhao et al. (2012)—The authors use a novel conditional mutant to show that neural Shh is essential for the proper development of the eye and hypophysis, a role that had escaped previous analyses.