The goal of this research project is to understand the function of the gene mutated in Rieger syndrome I, the pitx2 homeobox gene, during odontogenesis. Human patients with Rieger syndrome I, a haploinsufficient disorder, have tooth anomalies, anterior segment ocular defects, and umbilical defects as cardinal features. Using gene targeting in embryonic stem cells, we generated a mouse model of Rieger syndrome I. Pitx2 null mice had severe abnormalities in craniofacial and tooth morphogenesis. Moreover, we found that pitx2 null mutant oral ectoderm failed to express fgf8 and had expanded expression of Bmp4, suggesting that pitx2 has a role in regulating these signaling pathways. We have generated two new isoform-specific pitx2 mutant alleles. Analysis of pitx2 allelic combinations revealed a differential sensitivity of the fgf8 and Bmp-mediated signaling pathways to pitx2 dosage.
The first aim of this research program proposes to investigate the cellular mechanisms of pitx2 function in oral ectoderm using chimera analysis. We will also perform functional studies to probe the relationship between pitx2 and the Bmp4- and fgf8-signaling pathways. Finally, we propose to investigate pitx2c isoform-specific function in oral and dental epithelium. These studies will lead to fundamental advances in the understanding of the molecular genetic mechanisms underlying a human syndrome, Rieger syndrome I.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013509-04
Application #
6738103
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Small, Rochelle K
Project Start
2001-07-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2006-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$236,801
Indirect Cost
Name
Texas A&M University
Department
Type
Schools of Medicine
DUNS #
141582986
City
College Station
State
TX
Country
United States
Zip Code
77845
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Ma, Lijiang; Martin, James F (2005) Generation of a Bmp2 conditional null allele. Genesis 42:203-6
Liu, Wei; Sun, Xiaoxia; Braut, Alen et al. (2005) Distinct functions for Bmp signaling in lip and palate fusion in mice. Development 132:1453-61
Zhang, Zhen; Cerrato, Fabiana; Xu, Huansheng et al. (2005) Tbx1 expression in pharyngeal epithelia is necessary for pharyngeal arch artery development. Development 132:5307-15
Ma, Lijiang; Lu, Mei-Fang; Schwartz, Robert J et al. (2005) Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning. Development 132:5601-11
Selever, Jennifer; Liu, Wei; Lu, Mei-Fang et al. (2004) Bmp4 in limb bud mesoderm regulates digit pattern by controlling AER development. Dev Biol 276:268-79
Liu, Wei; Selever, Jennifer; Wang, Degang et al. (2004) Bmp4 signaling is required for outflow-tract septation and branchial-arch artery remodeling. Proc Natl Acad Sci U S A 101:4489-94
Liu, Wei; Selever, Jennifer; Lu, Mei-Fang et al. (2003) Genetic dissection of Pitx2 in craniofacial development uncovers new functions in branchial arch morphogenesis, late aspects of tooth morphogenesis and cell migration. Development 130:6375-85
Akiyama, Haruhiko; Chaboissier, Marie-Christine; Martin, James F et al. (2002) The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev 16:2813-28
Logan, Malcolm; Martin, James F; Nagy, Andras et al. (2002) Expression of Cre Recombinase in the developing mouse limb bud driven by a Prxl enhancer. Genesis 33:77-80

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