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First published online 16 February 2005
doi: 10.1242/dev.01676
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1 Alkek Institute of Biosciences and Technology, Texas A&M System Health
Science Center, 2121 Holcombe Boulevard, Houston, TX 77030, USA
2 Department of Molecular Genetics, University of Texas M.D. Anderson Cancer
Center, 1515 Holcombe Boulevard, Houston, TX 77030,USA
3 Laboratory of Reproductive and Developmental Toxicology, National Institutes
of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
4 Department of Pediatric Dentistry, School of Dental Medicine, University of
Connecticut Health Science Center, 263 Farmington Avenue, Farmington, CT
06030, USA
* Author for correspondence (e-mail: jmartin{at}ibt.tamhsc.edu)
Accepted 5 January 2005
Previous work suggested that cleft lip with or without cleft palate (CL/P) is genetically distinct from isolated cleft secondary palate (CP). Mutations in the Bmp target gene Msx1 in families with both forms of orofacial clefting has implicated Bmp signaling in both pathways. To dissect the function of Bmp signaling in orofacial clefting, we conditionally inactivated the type 1 Bmp receptor Bmpr1a in the facial primordia, using the Nestin cre transgenic line. Nestin cre; Bmpr1a mutants had completely penetrant, bilateral CL/P with arrested tooth formation. The cleft secondary palate of Nestin cre; Bmpr1a mutant embryos was associated with diminished cell proliferation in maxillary process mesenchyme and defective anterior posterior patterning. By contrast, we observed elevated apoptosis in the fusing region of the Nestin cre; Bmpr1a mutant medial nasal process. Moreover, conditional inactivation of the Bmp4 gene using the Nestin cre transgenic line resulted in isolated cleft lip. Our data uncover a Bmp4-Bmpr1a genetic pathway that functions in lip fusion, and reveal that Bmp signaling has distinct roles in lip and palate fusion.
Key words: Bmp, Palate, Morphogenesis
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