The long-term goal of this proposed research is to understand the molecular genetic mechanisms of craniofacial development and of orofacial cleft pathogenesis. Orofacial clefts, including cleft lip and cleft palate, are common birth defects that affect approximately 1 in 700 live births worldwide. Individuals with facial clefts undergo extensive surgical, dental, speech and psychological therapies that usually last for many years from infancy through the teenage years. Despite the frequent occurrence and extensive costly medical treatments associated with such birth defects, the causes and the pathogenic processes that lead to cleft lip and/or cleft palate are not well understood. Recent studies in animal model systems showed that development of the face, like development of other organs, are largely controlled by genetic factors. Indeed, there is accumulating evidence that specific gene mutations are associated with orofacial clefting. We have recently found that a spontaneous mutation, named Twirler, that causes cleft lip with cleft palate in homozygous mutant mice, is associated with alteration of the Zfhx1a gene. Interestingly, the Zfhx1a gene function is required for normal craniofacial development because a targeted disruption in this gene caused craniofacial defects including cleft palate in mice. The Zfhx1a gene is evolutionarily conserved and mutations in the human homolog causes multiple developmental defects. Moreover, the Zfhx1a gene product has been shown to interact with and regulate Bmp and Tgf-beta signaling, major molecular pathways regulating normal craniofacial development and involved in cleft lip/palate pathogenesis in mice and humans. Thus, we propose to determine the exact genetic lesion and the developmental mechanisms underlying facial cleft formation in the Twirler mutant mice. We will also determine the genetic interactions of Twirler/Zfhx1a with the Bmp/Tgf- beta signaling pathways during craniofacial development. These studies will greatly increase our understanding of the pathogenic mechanisms underlying orofacial cleft formation and will lead to development of methods for better diagnosis, treatment and/or prevention of orofacial clefting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE015207-10
Application #
8209293
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2003-04-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
10
Fiscal Year
2012
Total Cost
$363,641
Indirect Cost
$125,967
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Zhou, Jing; Gao, Yang; Lan, Yu et al. (2013) Pax9 regulates a molecular network involving Bmp4, Fgf10, Shh signaling and the Osr2 transcription factor to control palate morphogenesis. Development 140:4709-18
Liu, Han; Lan, Yu; Xu, Jingyue et al. (2013) Odd-skipped related-1 controls neural crest chondrogenesis during tongue development. Proc Natl Acad Sci U S A 110:18555-60
Jia, Shihai; Zhou, Jing; Gao, Yang et al. (2013) Roles of Bmp4 during tooth morphogenesis and sequential tooth formation. Development 140:423-32
Bush, Jeffrey O; Jiang, Rulang (2012) Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development. Development 139:231-43
Guillot, Nicolas; Kollins, Dmitrij; Gilbert, Victoria et al. (2012) BAMBI regulates angiogenesis and endothelial homeostasis through modulation of alternative TGF? signaling. PLoS One 7:e39406
Baek, Jin-A; Lan, Yu; Liu, Han et al. (2011) Bmpr1a signaling plays critical roles in palatal shelf growth and palatal bone formation. Dev Biol 350:520-31
Liu, Wenjin; Watson, Spencer S; Lan, Yu et al. (2010) The atypical homeodomain transcription factor Mohawk controls tendon morphogenesis. Mol Cell Biol 30:4797-807
Lan, Yu; Jiang, Rulang (2009) Sonic hedgehog signaling regulates reciprocal epithelial-mesenchymal interactions controlling palatal outgrowth. Development 136:1387-96
Liu, Wenjin; Lan, Yu; Pauws, Erwin et al. (2008) The Mn1 transcription factor acts upstream of Tbx22 and preferentially regulates posterior palate growth in mice. Development 135:3959-68
Chen, Jianquan; Bush, Jeffrey O; Ovitt, Catherine E et al. (2007) The TGF-beta pseudoreceptor gene Bambi is dispensable for mouse embryonic development and postnatal survival. Genesis 45:482-6

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