Role of Sonic Hedgehog in Development of the Central Nervous System

Abstract

Sonic hedgehog (Shh) functions as a morphogen to induce early dorso-ventral patterning of the central nervous system (CNS) and specifies cell fates of spinal motor neurons. Shh has also been known to promote cell cycle progression of embryonic stem cells as well as adult neural stem/progenitor cells. However, it has not been elucidated how Shh induces neural induction during early development of nervous system.

To elucidate the role of Shh in neural induction, we used a pluripotent embryonal carcinoma cell line, P19 and investigated the effects of Shh on inducing the expression of nestin, the marker for neural stem/progenitor cells. In early stages, we found that Shh promoted the CNS-specific enhancer of the nestin gene through regulation of E-box on nestin 2nd intron 5’-region by Nmyc that is a target gene of Shh signaling. Shh also increased population and proliferation of neural stem cells in vitro or in vivo. In late stages, Shh induced specification of motor neurons as well as dopaminergic neurons. Simultaneously, Shh inhibited the expression of meso-endoderm lineage markers, Gsc, Sox17, and GATA4. The results suggest that Shh promotes neurogenesis in multiple ways: by inducing the neuroectodermal cells, by repressing non-neural cell fates, and by promoting differentiation of neurally committed progenitor cells into motor and dopaminergic neurons.