Shh signaling in normal and pathological nervous system development

Funding Details
Canadian Institutes of Health Research
  • Grant type: Foundation Grant
  • Years: 2015/16 to 2019/20
  • Total Funding: $3,062,946
Keywords
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Project Summary

The morphogen Shh promotes proliferation and cell fate specification in the developing nervous system. In addition, we have shown that Shh is also an axon guidance molecule. This discovery led us to identify novel key players and novel molecular mechanisms in Shh signaling. We have expanded this initial work into a broader research program that encompasses complementary aspects of Shh signaling in the nervous system, namely cell fate specification and proliferation and developmental disorders and diseases. Thus my research program focuses on the molecular mechanism of Shh signaling in the nervous system and is centered around 3 interrelated subjects:A-Axon guidanceThe signaling pathway engaged by Shh to guide axons is different from the canonical Shh signaling pathway. We have shown that Shh-mediated axon guidance requires the receptor Boc and the signaling intermediate Src-family kinases (SFKs). Our objective is to understand how Shh activation of Boc and SFKs leads to the cytoskeletal changes required for growth cone turning. We are currently investigating the role of ß-arrestin as a scaffold that links Shh signaling with SFKs.We are also focusing on how cytoskeletal changes are mediated by Shh signaling toguide axons. We have shown that Shh activates Rac and Cdc42, two Rho GTPases that can regulate cytoskeletal dynamics. We have preliminary results implicating DOCKs, a Rho GTPase GEF in Shh-mediated axon guidance. These findings might directly link Shh signaling to cytoskeletal changes and will give us a comprehensive understanding of Shh signaling in axon guidance.B-Embryonic developmentWe have shown that Boc and Gas1 are co-receptors that form a complex with Ptch to receive the Shh signal in proliferation and cell fate specification. Our objective is to understand at the molecular and atomic level how the Shh receptor complex functions. In collaboration with C. Siebold (UK), a crystallographer, we have now elucidated the Gas1 structure and are pursuing co-crystals with Shh and the various receptor complex combinations with Ptch. This will allow us to understand the molecular mechanism of Shh receptor function and the functional implications of mutations in these receptors for Shh-dependent developmental disorders such as holoprosencephaly.C-Medulloblastoma tumorigenesisWe have recently found that Boc promotes the progression of medulloblastoma, a Shh-dependent brain tumor. Interestingly, Boc promotes tumor progression by enhancing DNA damage, thus increasing the frequency of mutations. Our objective is to understand how Boc induces DNA damage, which is a novel function for Boc.Gas1 is also upregulated in medulloblastomas, similarly to Boc. We will also determine whether Gas1 contributes to medulloblastoma tumorigenesis. This will be interesting as inactivation of Boc did not completely abolish tumorigenesis, suggesting that Gas1 might also play an oncogenic role.In summary, our fundamental work on Shh signaling and its reception has brought us to study their relevance in pathological conditions, such as medulloblastoma. Our objective is to expand our multifaceted fundamental research on Shh signaling and use our findings to instruct our work on Shh-related pathological conditions.