The process of human development is controlled by programs of regulated gene expression within the embryo. Birth defects are a major cause of morbidity and mortality in the pediatric population and thus represent a significant public health problem. Malformation syndromes result from gastric or environmental factors that disrupt developmentally-regulated programs of gene expression. Transcription factors are mediators of the genetic programs that define embryogenesis. Homeobox genes encode transcription factors containing a 60 amino acid domain that is capable of binding to DNA and these genes play essential roles in development. Msx-1 nd Msx-2 are homeodomain proteins that are expressed in developing cardiac, limb, and craniofacial structures during mammalian embryogenesis, especially at sites of important epithelio-mesenchymal inductive tissue interactions. Craniosynostosis, Boston type is a malformation syndrome with autosomal dominant inheritance that affects limb and craniofacial development. A mutation in the human MSX2 gene has been demonstrated in patients with this disorder that results in a substitution of histidine for an evolutionarily-conserved prokine residue at position 7 of the homeodomain. The long-term goal of the proposed research is to determine the role that MSX-1 and MSX-2 homeodomain proteins play in normal craniofacial development and the mechanisms by which mutations in the genes encoding these proteins may result in human craniofacial malformation syndromes.
The specific aims of this project are (i) to establish the pathogenesis of craniosynostosis, Boston type by molecular biologic and embryologic analyses of mutant and wild-type Msx-2 protein expression in vitro within tissue culture cells and in vivo murine development;l and (ii) to determine whether disruption of normal Msx-1 expression during murine development also results in a craniofacial malformation syndrome. These studies will further our understanding of the role of Msx proteins in craniofacial development, provide model systems for the study of craniofacial malformations, and establish a crucial link between the function of Msx proteins as putative transcriptional regulatory factors and their role in directing craniofacial development during human embryogenesis.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Specialized Center (P50)
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Johns Hopkins University
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Zumpano, Michael P; Richtsmeier, Joan T (2003) Growth-related shape changes in the fetal craniofacial complex of humans (Homo sapiens) and pigtailed macaques (Macaca nemestrina): a 3D-CT comparative analysis. Am J Phys Anthropol 120:339-51
Richtsmeier, Joan T; DeLeon, Valerie Burke; Lele, Subhash R (2002) The promise of geometric morphometrics. Am J Phys Anthropol Suppl 35:63-91
Zeiger, Joanna S; Beaty, Terri H; Hetmanski, Jacqueline B et al. (2002) Genetic and environmental risk factors for sagittal craniosynostosis. J Craniofac Surg 13:602-6
DeLeon, V B; Zumpano, M P; Richtsmeier, J T (2001) The effect of neurocranial surgery on basicranial morphology in isolated sagittal craniosynostosis. Cleft Palate Craniofac J 38:134-46
Paznekas, W A; Okajima, K; Schertzer, M et al. (1999) Genomic organization, expression, and chromosome location of the human SNAIL gene (SNAI1) and a related processed pseudogene (SNAI1P). Genomics 62:42-9
Boyadjiev, S A; Jabs, E W; LaBuda, M et al. (1999) Linkage analysis narrows the critical region for oculodentodigital dysplasia to chromosome 6q22-q23. Genomics 58:34-40
Zumpano, M P; Carson, B S; Marsh, J L et al. (1999) Three-dimensional morphological analysis of isolated metopic synostosis. Anat Rec 256:177-88
Cole 3rd, T M; Richtsmeier, J T (1998) A simple method for visualization of influential landmarks when using euclidean distance matrix analysis. Am J Phys Anthropol 107:273-83
Richtsmeier, J T; Cole 3rd, T M; Krovitz, G et al. (1998) Preoperative morphology and development in sagittal synostosis. J Craniofac Genet Dev Biol 18:64-78
Cohen, M E; Yin, M; Paznekas, W A et al. (1998) Human SLUG gene organization, expression, and chromosome map location on 8q. Genomics 51:468-71

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