Complex gene regulatory networks and signaling cascades must be carefully regulated both spatially and temporally in order to orchestrate the formation of different tissues and organ systems. Epigenetic regulators and chromatin remodelers add a hierarchal level of control to the timely activation or repression of key developmental processes.

The formation of the craniofacial skeleton requires precise organization of tightly regulated cellular and molecular processes across multiple cell types and tissues. Important to proper formation of the craniofacial complex is the development of cranial neural crest cells. This dynamic multipotent population of cells must undergo an epithelial-to-mesenchymal transition, migrate toward the pharyngeal arches and then begin differentiation toward chondrocytes and osteoblasts to form the cartilage and bone of the developing face, as well as neurons and glia of the peripheral nervous system. Alterations to gene regulatory networks or signaling modules that govern cranial neural crest cell differentiation toward chondrocytes, osteoblasts and neurons can impact the development of these structures and lead to craniofacial defects including mandibular hypoplasia, cleft lip/palate, and middle ear defects, among others.

While the processes of cranial neural crest-derived derivative differentiation and maturation have been well characterized, the upstream temporal and spatial regulation of the gene regulatory networks and signaling pathways facilitating these processes remain largely unknown.

Our lab focuses on investigating the conserved and diverging functional roles for chromatin remodelers/transcription factors from the PRDM histone methyltransferase family, PRDM3 and PRDM16 in zebrafish and mouse craniofacial development. These factors have roles for these two PRDMs in facilitating proper chondrocyte differentiation and maturation during craniofacial development. I have found that these paralogs function antagonistically of each other to balance Wnt/beta-catenin signaling both at the transcriptional and chromatin level. Loss of either leads to dysregulated Wnt/beta-catenin signaling which alters neural crest chondrocyte differentiation and maturation leading to compromised formation of craniofacial cartilage structures (Shull et al, Development 2022).

The Shull lab will build upon these findings to explore new mechanisms of transcriptional and epigenetic regulation during the critical stages of cartilage and bone formation during craniofacial development.