Sonic hedgehog in vertebrate neural tube development (2018)

The formation and wiring of the vertebrate nervous system involves the spatially and temporally ordered production of diverse neuronal and glial subtypes that are molecularly and functionally distinct. The chick embryo has been the experimental model of choice for many of the studies that have led to our current understanding of this process, and has presaged and informed a wide range of complementary genetic studies, in particular in the mouse. The versatility and tractability of chick embryos means that it remains an important model system for many investigators in the field. Here we will focus on the role of Sonic hedgehog (Shh) signaling in coordinating the diversification, patterning, growth and differentiation of the vertebrate nervous system. We highlight how studies in chick led to the identification of the role Shh plays in the developing neural tube and how subsequent work, including studies in the chick and the mouse revealed details of the cell intrinsic programs controlling cell fate determination. We compare these mechanisms at different rostral-caudal positions along the neuraxis and discuss the particular experimental attributes of the chick that facilitated this work.

The secretion, spread and reception of Shh within the neural tube depends on a large set of dedicated proteins, many of which are highly conserved

The route by which Shh protein is dispersed through the posterior neuroepithelium remains unclear.

microtubule based transport traffics Shh from the notochord across cells in the midline of the forming neural tube (the prospective floor plate), possibly in vesicles, to their apical surface, where it is released

it is clear that several extracellular and transmembrane proteins influence the spread of Shh protein through the neuroepithelium.

Collectively, the studies of the last two decades have revealed the multiple roles that Shh plays in the development of the vertebrate nervous system. Reciprocally, the analysis of neural tube development has provided multiple insights into Shh signaling. The chick embryo has featured prominently in many of these studies and through this work we have gained new mechanistic insights into how a single signal can perform several functions and produce an ordered pattern of diverse cell types in a complex tissue. Not only have these insights deepened our understanding of fundamental developmental processes but they have also been a major influence in the establishment of methods for the directed differentiation of specific neuronal subtypes from embryonic stem cells in vitro (Wichterle et al., 2002); Cundiff and Anderson, 2011; Liu and Zhang, 2010). Moreover the transplantation of stem cell-derived neurons back into chick has resulted in successful engraftment (Wichterle et al., 2002), raising the hope that this could provide an eventual route to cell based therapies for some neurodegenerative diseases.

Despite the progress, much remains to be discovered about Shh signaling and neural tube development. Approaches that provide live, high-resolution measurements of the activity of key components of the pathway are necessary to decipher the signaling mechanism and provide insight into the dynamics of signal transmission through the pathway. Similarly, understanding how Shh signaling regulates differential gene expression to control cell fate decisions will benefit from the increased precision and resolution that new technologies are beginning to offer. It seems likely that the chick will continue to play a leading role in these approaches.