Transcriptional Targets of PDGF Signaling during Craniofacial Development

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

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Abstract

DESCRIPTION (provided by applicant): Craniofacial defects, such as cleft lip and/or palate, are the most prevalent congenital malformations worldwide. The cranial neural crest, an essential contributor to the facial skeleton, requires platelet derived growth factor (PDGF) signaling. In humans, SNPs in the PDGFC regulatory region are associated with cleft lip and palate. In mice, loss of PDGF Receptor ¿ (PDGFR¿) or its ligands, PDGFA and PDGFC, results in facial clefting. Previous work has shown that PDGFR¿ is required cell autonomously in the neural crest for craniofacial development. My project focuses on determining novel transcriptional pathways downstream of PDGFR¿ critical for craniofacial development. We adopted a next generation sequencing approach using mouse embryonic palatal mesenchyme (MEPM) cells to identify PDGF responsive genes on a genome wide scale in a physiologically relevant system. To this end, we stimulated primary mouse embryonic palatal mesenchyme (MEPM) cells with PDGFA and performed RNA-seq at 0, 1, and 4 hours. Analysis of this dataset yielded seven candidate transcriptional pathways regulated by PDGF signaling. To limit the scope of our studies for this proposal, we focus on Serum Response Factor (SRF), an important transcriptional regulator of actin dynamics that we found compelling given the classic function of PDGF in modulating the actin cytoskeleton. Mice harboring conditional deletion of SRF in the neural crest display both cardiac and craniofacial defects; excitingly, further investigation uncovered a previously unreported overt facial cleft in these mice. In addition, many transcriptional targets of SRF (ActB, FlnA, and MyH9) are implicated in human craniofacial development. By studying the interactions between PDGF signaling and SRF activity, we will build the foundation required to design innovative diagnostic and therapeutic strategies targeting these fundamental pathways.