Functions of PRDM Histone Methyltransferases during Cartilage Development in the Craniofacial Skeleton

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Chondrocytes derived from cranial neural crest cells give rise to cartilaginous structures that form the craniofacial skeleton. These cells must undergo numerous cellular processes including condensation, orientation, intercalation, proliferation, differentiation, and maturation before forming a template that will serve as a scaffold for subsequent bone formation. The gene regulatory networks (GRNs) and signaling pathways, controlling these processes need to be tightly regulated. Any alteration to the GRNs or signaling modules during chondrocyte maturation and differentiation can compromise the skeletal integrity of the developing craniofacial tissues and contribute to the etiology of congenital defects including but not limited to cleft lip with or without cleft palate, mandibular hypoplasia, craniosynostosis. I am interested in understanding how the chromatin modifiers, Prdm3 and Prdm16, epigenetically control spatial and temporal gene expression during craniofacial development. The aims outlined in this proposal utilize molecular, genetic and epigenetic tools in both zebrafish and mice to test the hypothesis that Prdm3 and Prdm16 act upstream of Wn/β-catenin to properly balance chondrocyte functionality during the formation of the craniofacial complex. In Aim 1, the molecular mechanisms controlling Wnt/β-catenin transcriptional activity in chondrocytes during zebrafish craniofacial development will be defined. The conserved functions of chondrocyte polarity and differentiation through regulation of Wnt/β-catenin will be identified in the mammalian craniofacial complex (Aim 2), and lastly, the functions of conserved Prdm3- and Prdm16-regulated canonical Wnt/β-catenin enhancers across vertebrates in the craniofacial mesenchyme will be assessed (Aim 3). Completion of these aims will provide insight on how these epigenetic modifiers control specific GRNs and signaling modules (Wnt/β-catenin) to facilitate proper chondrogenesis in formation of the craniofacial skeleton. Importantly, this project will also provide mechanistic insight behind how loss of these factors contributes to the development of craniofacial disorders. The research training plan along with the career development and mentorship plan outlined in this proposal are designed to provide the foundation for my career goal of becoming an independent investigator at a top research institution. During the K99 phase, I will receive mentorship in zebrafish biology from Kristin Artinger, as well as guidance from members on my advisory committee for mouse craniofacial biology and bioinformatics analysis. An extensive career development plan with activities promoting grant writing, scientific communication, and leadership and mentoring skills, in alignment with the MOSAIC program, will facilitate my transition to an independent faculty position during the R00 phase. The Craniofacial Department at the University of Colorado Anschutz Medical Campus offers an exceptional environment with countless resources to conduct this research and training plan that will guide my success toward reaching my career goals.