Fetal development of the mammalian craniofacial region is a complex embryological process which is poorly understood at the molecular level. Early in embryonic life the mammalian craniofacial region is first manifested as a blastema-like structure of paired branchial arches comprised primary of neural crest-derived mesenchymal cells. These neural crest cells acquires some of their patterning information prior to emigration from the hindbrain, and additional patterning information is imparted to them during their migration into the branchial arches. Several homeobox-containing DNA-binding transcriptional regulations have been identified which direct certain aspects of the morphogenesis and cellular differentiation of the craniofacial region. Here we describe a Dlx5 a new homeobox-containing gene of the distal less (Dlx) family which is most strongly expressed in the mesenchyme of the developing craniofacial region. Based upon its embryonic expression pattern, and the mode of action of other Dlx homeobox-contain genes, Dlx5 has the potential of being a major director normal morphogenesis and cellular differentiation of branchial arch derived structures. To understand the genetic basis of embryonic development of the craniofacial region, we propose to alter the normal function of the homeobox Dlx5 which shows highly restricted expression in the branchial arches (as well as the perichondrial region of all skeletal elements). In addition, we will identify and characterize the DNA cis-regulatory elements which direct regionally-restricted Dlx5 gene expression in the developing craniofacial region. To this end, we will rely primarily on the transgenic mouse technology that we have developed and refined over the last eight years. Accordingly, (I) we will generate a disruption (gene knock-out) of Dlx5. (II) We will determine the DNA regulatory elements which control Dlx5 craniofacial-specific gene expression. Results of these experiments will help clarify the role of Dlx5 in normal craniofacial morphogenesis. This is in keeping with our long range goal which is to understand the molecular mechanisms involved in directing mammalian craniofacial development with the belief that such knowledge will eventually be used to correct either trauma to, or genetic defects of the craniofacial region.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Comprehensive Center (P60)
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Mount Sinai School of Medicine
New York
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Yang, Jie; Zhu, Wei; Chen, Jiansong et al. (2014) Genome-wide two-marker linkage disequilibrium mapping of quantitative trait loci. BMC Genet 15:20
Beaty, T H; Taub, M A; Scott, A F et al. (2013) Confirming genes influencing risk to cleft lip with/without cleft palate in a case-parent trio study. Hum Genet 132:771-81
Skare, Oivind; Jugessur, Astanand; Lie, Rolv Terje et al. (2012) Application of a novel hybrid study design to explore gene-environment interactions in orofacial clefts. Ann Hum Genet 76:221-36
Wehby, G L; Tyler, M C; Lindgren, S et al. (2012) Oral clefts and behavioral health of young children. Oral Dis 18:74-84
Shaffer, J R; Wang, X; Feingold, E et al. (2011) Genome-wide association scan for childhood caries implicates novel genes. J Dent Res 90:1457-62
Schneider, Galen B; Zaharias, Rebecca; Seabold, Denise et al. (2011) Integrin-associated tyrosine kinase FAK affects Cbfa1 expression. J Orthop Res 29:1443-7
Larjava, H; Koivisto, L; Häkkinen, L et al. (2011) Epithelial integrins with special reference to oral epithelia. J Dent Res 90:1367-76
Jugessur, Astanand; Shi, Min; Gjessing, Håkon Kristian et al. (2010) Maternal genes and facial clefts in offspring: a comprehensive search for genetic associations in two population-based cleft studies from Scandinavia. PLoS One 5:e11493
Jugessur, Astanand; Shi, Min; Gjessing, Håkon Kristian et al. (2009) Genetic determinants of facial clefting: analysis of 357 candidate genes using two national cleft studies from Scandinavia. PLoS One 4:e5385
Cottrell, Catherine E; Sommer, Annemarie; Wenger, Gail D et al. (2009) Atypical X-chromosome inactivation in an X;1 translocation patient demonstrating Xq28 functional disomy. Am J Med Genet A 149A:408-14

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