Grant: Project Grant

Dissecting the molecular events sustaining organogenesis is essential to comprehend the cause of developmental disorders, and to contemplate cures using regenerative medicine approaches. Yet, our understanding of the mechanisms that coordinate cytoskeletal dynamics required for tissue morphogenesis remains rudimentary. Due to their ability to orchestrate cytoskeletal rearrangements, Rho GTPases are key regulators of tissue morphogenesis. In mammals, there are 20 Rho GTPases and nearly 150 regulators that are part of the RhoGEFs, RhoGAPs and RhoGDIs families. However, only a few molecules from these networks have been studied in depth. The mouse skin is an ideal system to study morphogenesis processes since it develops through a succession of sophisticated cellular rearrangements, but the molecular details of these processes remain poorly comprehended. Moreover, it is amenable to in utero lentiviral injections, a method that dramatically improved our ability to genetically modify this tissue. Using this technology, we developed a high throughput screening methodology that allowed the identification of new regulators of skin morphogenesis among the Rho GTPase signaling networks. Strikingly, we discovered that depletion of the understudied RhoGEF ARHGEF3 reduced the number of hair follicle that formed during embryonic development. Remaining hair follicles are misoriented and form lesions that are associated with the expansion hair follicle stem cells. Using state-of-the-art multidisciplinary approaches such as lentiviral injection, cell imaging and proteomic, this CIHR program focus on understanding the role of ARHGEF3 during skin development and regeneration. This work will provide fundamental insights into the molecular mechanisms that regulate skin development and it will be the first analysis of the function of ARHGEF3 in this tissue. Additionally, this work will contribute to our knowledge of how Rho GTPase signaling regulates tissue stem cells activity.