Neural crest cells (NCCs) are pluripotent cells that migrate from the developing neural tube to populate various tissues including craniofacial structures, neurons and glia of the peripheral nervous system, and pigment cells. Improper migration and development of NCCs can lead to a variety of birth defects collectively termed neurocristopathies. To become migratory, NCCs undergo epithelial to mesenchymal transition (EMT). EMTs at the wrong place and time are associated with cancer progression, invasion, and metastasis among other pathological events. Thus, it is critically important to have a complete understanding of the biology of EMT. While some work has focused on identifying signals that induce EMT, much of it was done in cells outside of their natural environment, which has a great effect on cell signaling and behavior. I have focused on the physical behaviors NCCs use to carry out EMT in vivo and this proposal will test how specific molecules, namely the GTPase Rho and Cadherin-6, control these behaviors.
My specific aims are to 1.) Image the distribution and level of active Rho during NCC EMT 2.) Determine the effects of Rho manipulation on dynamic cell behavior and F-actin. 3.) Determine whether Rho and Cad-6 cooperate to promote NCC EMT. These experiments will begin to define molecular pathways that control EMT in vivo and have the potential inform therapies for treatment of pathologies involving abnormal cell migration and EMT.
Improper development of neural crest cell (NCC) derived structures, including craniofacial bone and cartilage, leads to a class of birth defects called neurocristopathies. To populate their targets NCCs must become migratory, which involves undergoing epithelial to mesenchymal transition (EMT). EMTs are important events in development that also drive pathologies such as fibrosis, chronic inflammation, and cancer metastasis. The experiments proposed here have the potential to explain how specific molecules control these critical events and inform therapies in diseases involving EMT and abnormal cell migration.
|Clay, Matthew R; Halloran, Mary C (2014) Cadherin 6 promotes neural crest cell detachment via F-actin regulation and influences active Rho distribution during epithelial-to-mesenchymal transition. Development 141:2506-15|
|Clay, Matthew R; Halloran, Mary C (2013) Rho activation is apically restricted by Arhgap1 in neural crest cells and drives epithelial-to-mesenchymal transition. Development 140:3198-209|