During development, neural crest cells give rise to craniofacial skeleton. Craniofacial disorders resulting from disruptions in this process are among the most common birth defects. The FGF signaling pathway has been implicated in a number of craniofacial syndromes including Crouzon, Apert, Muenke, DiGeorge, Kallman, Crouzon, and Saethre-Chotzen syndromes. Identifying and understanding the developmental roles of the FGF signaling pathway in craniofacial development is therefore of major importance to human health. Conditional inactivation of Fgfr1 in neural crest cells results in cleft palate and frontonasal dysplasia but no studies have identified the precise function of Fgfr1 in these cells.
The aims of this proposal are to (1) identify the cellular processes mediated by Fgfr1 in cranial neural crest cells and (2) identify the intracellular signaling pathways utilized by Fgfr1 to initiate these processes. To achieve these aims I will utilize conditional mouse genetics to disrupt Fgfr1 function in neural crest cells. I will monitor proliferation, migration, apoptosis and patterning i vivo to determine the cellular processes Fgfr1 mediates in craniofacial development. In parallel, I have generated mice harboring an allelic series of point mutations designed to disrupt the ability of Fgfr1 to utilize various intracellular signaling pathways. I will evaluate these mutantsfor neural crest cell and craniofacial phenotypes, to elucidate how Fgfr1 signaling pathways are utilized in these contexts. This proposal will therefore provide a detailed, mechanistic understanding of how Fgfr1 functions in normal craniofacial development.
This project seeks to identify how fibroblast growth factor receptor 1 (Fgfr1) utilizes various intracellular signaling pathways to confer its function in craniofacial development. Fgfr1 is crucial for normal development and has been implicated in numerous congenital and neoplastic disorders. Understanding how Fgfr1 normally functions is therefore critically important to identifying how signaling has gone awry in Fgf related pathologies.
|Brewer, J Richard; Mazot, Pierre; Soriano, Philippe (2016) Genetic insights into the mechanisms of Fgf signaling. Genes Dev 30:751-71|
|Brewer, J Richard; Molotkov, Andrei; Mazot, Pierre et al. (2015) Fgfr1 regulates development through the combinatorial use of signaling proteins. Genes Dev 29:1863-74|