1) Studying the expression and regulation of transcription factor genes and signaling processes involved in craniofacial/tooth development
We work on the hierarchical interactions of homeodomain, T-box, forkhead domain and Lim domain transcription factors in craniofacial/tooth development. These transcription factors interact separately or in concert together or with other factors to regulate gene expression in a temporal and spatial mechanism. The function and interaction of these factors plays a major role in the timing and development of teeth and craniofacial tissues.
The planar cell polarity effector gene, Fuz, and FoxJ1 transcription factor coordinate cell polarity, ciliogenesis, Hedgehog (Hh) and Wnt signaling and gene expression during dental and craniofacial development. Fuz signaling mechanisms are both cilia dependent and cilia independent and both mechanisms regulate different signaling pathways. The Fuz null mice have massive craniofacial defects including cleft palate and tooth agenesis. FoxJ1 null mice have late stage tooth developmental anomalies affecting enamel formation. Our studies have uncovered a link between these two factors regulating both cilia and craniofacial/tooth development. We are working to understand the role of Fuz and FoxJ1 in human birth defects. Our newly identified human FUZ mutations are critical to understanding the molecular basis of FUZ in developmental anomalies.
2) The molecular basis of selected human genetic disorders
We are using mouse models to help understand the genes involved in many human genetic disorders. A couple examples are Axenfeld-Rieger syndrome (ARS), where mutations in the transcription factor Pitx2 have been associated with ARS, and DiGeorge syndrome (DGS), associated with Tbx1 mutations.
3) The role of stem cells and microRNAs in regulating craniofacial and regenerative medicine.
We are currently using microRNAs (miRs) to control stem cell development and to regenerate tissues. We have begun to demonstrate a hierarchy of dental epithelial expressed transcription factors in regulating gene expression networks required for tooth morphogenesis. Dental miRs control stemness properties of the dental progenitors cells and we have identified several novel miR transcription factor targets. These targets also function in many other developmental processes. We are using miRs to program embryonic stem cells and reprogrammed dental progenitor cells.