Craniofacial malformations, including cleft lip and palate, are common disfiguring birth defects in humans, occurring at a frequency of approximately 1 in 600 infants. The causes of such birth defects are complex, involving multiple genetic and environmental factors. To gain a better understanding of the molecular mechanisms underlying normal craniofacial development and the pathogenic processes leading to congenital craniofacial malformations, we are using a combination of genetic, biochemical, and embryological approaches to analyze craniofacial development in the model mammalian system, the laboratory mice. We are using both forward and reverse genetic approaches to investigate the molecular mechanisms of craniofacial birth defects. The forward genetic approach involves identification of causal genes and molecular pathways disrupted by uncharacterized mutations that cause craniofacial malformations including cleft lip and/or cleft palate (e.g., we recently positionally cloned the classic orofacial cleft mutation Dancer), whereas the reverse genetic approach involves generation and analyses of mice carrying null or conditional mutations using the Cre/loxP-mediated gene targeting techniques. Current gene targeting projects focus on investigating the roles of transcription factors and signaling molecules exhibiting tissue specific expression patterns during craniofacial development. In the last few years, we have analyzed more than five different mutant mouse strains with craniofacial developmental defects. Using these mutant mouse models, we are attempting to delineate the molecular pathways and to identify novel genes that interact with known critical regulators of craniofacial development using genetic modifier screening, genomic manipulations, microarray-based gene expression profiling, as well as protein-protein interaction studies. These studies are providing new insights into the molecular genetic mechanisms underlying human craniofacial development and birth defects.

Krebs, L. T., Iwai, N., Nonaka, S., Welsh, I. C., Lan, Y., Jiang, R., Saijoh, Y., O'Brien, T. P., Hamada, H., and Gridley, T. (2003). Notch signaling regulates left-right asymmetry determination by inducing Nodal expression. Genes & Development 17:1207-1212.

Bush, J. O., Maltby, K. M., Cho, E.-S., and Jiang, R. (2003). The T-box gene Tbx10 exhibits a uniquely restricted expression pattern during mouse embryogenesis. Gene Expression Patterns 3:533-538.

Lan, Y., Ovitt, C. E., Cho, E.-S., Maltby, K. M., Wang, Q., and Jiang, R. (2004) Odd-skipped related 2 (Osr2) encodes a key intrinsic regulator of secondary palate growth and morphogenesis. Development 131:3207-3216.

Bush, J. O., Lan, Y., and Jiang, R. (2004). The cleft lip and palate defects in the Dancer mutant mice result from gain of function of the Tbx10 gene. Proceedings of the National Academy of Sciences USA 101:7022-7027.

Hadland, B. K., Huppert, S., Kanungo, J., Xue, Y., Jiang, R., Gridley, T., Colon, R. A., Cheng, A. M., Kopan, R. and Longmore, G. D. (2004). A requirement for Notch1 distinguishes two phases of definitive hematopoiesis during development. Blood 104:3097-3105.

Alappat, S. R., Zhang, Z., Suzuki, K., Zhang, X., Jiang, R., Yamada, G. and Chen, Y. (2005). The cellular and molecular etiology of cleft secondary palate in Fgf10 mutant mice. Developmental Biology 277:102-113.