Receptor tyrosine kinases (RTKs) bind to growth factors at the cell surface and activate various intracellular signaling pathways to elicit responses with broad roles in developmental cellular processes. A subset of RTK families have been shown to regulate the activity of neural crest cells (NCCs) and the development of their derivatives in mammalian systems. NCCs are migratory, multipotent cells that play a critical role in vertebrate development. NCCs can be subdivided into four axial populations, cranial, cardiac, vagal, and trunk, which migrate throughout the embryo along defined pathways and give rise to a diverse array of cell types and structures. Cranial NCCs originate from the forebrain to the hindbrain and populate the frontonasal prominence and pharyngeal arches 1-4. These cells give rise to the bone and cartilage of the frontonasal skeleton, among other derivatives.
Our lab is focused on investigating the mechanism and function of signaling through a particular RTK family, the platelet-derived growth factor (PDGF) receptor family, in development of the cranial NCC-derived craniofacial skeleton. Further, we are interested in exploring the broader role of the PDGF family in mediating regional specificity throughout the mouse embryo. Signaling through PDGFRα plays a critical role in craniofacial development; mutant mouse models of the gene display phenotypes ranging from a cleft palate to shortening of the frontonasal masses and complete facial clefting. Functional analysis of PDGFRα signaling during mouse development has revealed roles in promoting migration of NCCs and proliferation and survival of the NCC-derived craniofacial mesenchyme. Recently, we have revealed a role for the other RTK in this family, PDGFRβ, in murine nasal septum and palatal shelf development. Despite these advances, several outstanding questions remain regarding the contribution of PDGFRα and PDGFRβ to development of the facial midline.
Our goal is to characterize novel intracellular pathways and cellular processes engaged downstream of PDGF receptor induction, as well as tissue-specific regulation of receptor expression throughout the mouse embryo. We utilize an array of complementary approaches such as phosphoproteomics, next-generation sequencing, conditional mutagenesis in the mouse embryo and in vitro primary cell activity assays to explore novel aspects of craniofacial biology and ultimately, provide therapeutic directions aimed at the treatment of human birth defects.