Cleft palate is a common birth defect in humans. To understand the molecular and cellular mechanisms of cleft palate pathogenesis, we have been investigating the molecular pathways governing normal palate development in the laboratory mice. Through gene expression screens, we have identified several genes encoding putative transcription factors that exhibit distinct and dynamic expression patterns during the palate development. Using the gene targeting technology, we have generated mice carrying null or conditional null mutations in some of these transcription factor genes. Analyses of the mutant mice revealed that several newly identified transcription factors, such as Osr1 and Osr2, play essential roles in palate development. Ongoing investigations focus on delineating the molecular pathways involving these factors in palate development using a combination of genetic, embryological, and biochemical approaches.

Casey, L. M., Lan, Y., Cho, E.-S., Maltby, K. M., Gridley, T. and Jiang, R. (2006). Jag2-Notch1 signaling regulates oral epithelial differentiation and palate development. Developmental Dynamics 235:1830-1844.

Lan, Y., Ryan, R. C., Zhang, Z., Bush, J. O., Maltby, K. M., Bullard, S. A., Lidral, A. C. and Jiang, R. (2006). Expression of Wnt9b and activation of canonical Wnt signaling during midfacial morphogenesis in mice. Developmental Dynamics 235:1448-1454.

Liu, H., Liu, W., Maltby, K. M., Lan, Y. and Jiang, R. (2006). Identification and developmental expression analysis of a novel homeobox gene closely linked to the mouse Twirler mutation. Gene Expression Patterns (Mechanisms of Development) 6:632-636.

Wang, Q., Lan, Y., Cho, E.-S., Maltby, K. M. and Jiang, R. (2005). Odd-skipped related 1 (Odd1) is an essential regulator of heart and urogenital development. Developmental Biology 288:582-594.

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.

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.

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., Lan, Y., Maltby, K. M. and Jiang, R. (2002). Isolation and developmental expression analysis of Tbx22, the mouse homolog of the human X-linked cleft palate gene. Developmental Dynamics 225:322-326 8.

Carver, E. A., Jiang, R., Lan, Y., Oram, K. F. and Gridley, T. (2001). The mouse Snail gene encodes a key regulator of the epithelial-mesenchymal transition. Molecular and Cellular Biology 21:8184-8188.

Lan, Y., Kingsley, P. D., Cho, E. S. and Jiang, R. (2001). Osr2, a new mouse gene related to Drosophila odd-skipped exhibits dynamic expression patterns during craniofacial, limb, and kidney development. Mechanisms of Development 107:175-179.

McCright, B., Gao, X., Lozier, J., Lan, Y., Shen, L., Maguire, M., Herzlinger, D., Weinmaster, G., Jiang, R. and Gridley, T. (2001). Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation. Development 128:491-502.

Lanford, P.J., Lan, Y., Jiang, R., Lindsell, C., Weinmaster, G., Gridley, T. and Kelley, M.W. (1999). Notch signaling mediates Hair cell development in mammalian cochlea. Nature Genetics 21:289-292.

Jiang, R., Lan, Y., Norton, C.R. and Gridley, T. (1998). The Slug gene is not essential for mesoderm or neural crest development in mice. Developmental Biology 198:277-285.

*Jiang, R., * Lan, Y., Chapman, H.D., Shawber, C., Norton, C.R., Serreze, D.V., Weinmaster, G. and Gridley, T. (1998). Defects in limb, craniofacial and thymic development in Jagged2 mutant mice. Genes & Development 12:1046-1057. (* co-first authors).

Bell, S., Lan, Y., Jiang, R. and Gridley, T. (1998). Exclusion of Jagged2 as a candidate for the legless gene. Mammalian Genome 9:778-779.

Lan, Y., Fujioka, M., Polsgrove, R., Miskiewicz, P., Morrissey, D., Goto, T. and Weir, M. (1998). Plasticity of Drosophila Paired function. Developmental Genetics, 23:45-55.

Lan, Y., Jiang, R., Shawber, C., Weinmaster, G. and Gridley, T. (1997). The Jagged2 gene maps to chromosome 12 and is a candidate for the lgl and sm mutations. Mammalian Genome 8:875-876

Casirola, D.M., Lan, Y. and Ferraris, R.P. (1997). Effects of changes in calorie intake on intestinal nutrient uptake and transporter mRNA levels in aged mice. Journal of Gerontology, 52:B300-3109.

*Miskiewicz, P., *Morrissey, D.,* Lan, Y., Raj, L., Kessler, S., Fujioka, M., Goto, T. and Weir, M. (1996). Both the paired domain and homeodomain are required for in vivo function of Drosophila Paired. Development, 122:2709-2718. (* co-first authors)

Cai, J., Lan, Y., Appel, L.F. and Weir, M. (1994). Dissection of the Drosophila Paired protein: Functional requirements for conserved motifs. Mechanisms of Development, 47:139-150.

Anathan, J., Baler, R., Morrissey, D., Zou, J., Lan, Y., Weir, M. and Voellmy, R. (1993). Synergistic activation of transcription is mediated by the N-terminal domain of Drosophila fushi tarazu homeoprotein and can occur without DNA binding by the protein. Molecular and Cellular Biology, 13:1599-1609.