Cleft lip and palate is a common congenital anomaly with significant lifelong morbidity. The extensive psychological, surgical, speech and dental involvement emphasize the importance of understanding the underlying causes. Our long-term objective is to discover the genes and environmental factors that contribute to this disorder. However, the etiology of cleft lip and palate is complex, and given the large number of genes predicted to be involved in isolated cleft lip and palate, gene discovery poses a significant challenge. The approach used here will be to study a genetically simple model of orofacial clefting, Van der Woude syndrome. Van der Woude syndrome is an outstanding clinical model for isolated cleft lip and palate, as its only distinguishing features are pits in the lower lip. Mutations in Interferon Regulatory Factor 6 (IRF6) cause Van der Woude syndrome. Moreover, genetic variation in IRF6 confers risk for isolated cleft lip and palate, demonstrating that Van der Woude syndrome is also an outstanding genetic model. Thus, IRF6 is essential for a critical pathway in palate development, and its discovery represents a foothold in this pathway. The main goal of this proposal is to delineate the IRF6 pathway by first determining the in vivo function of IRF6 and then identifying factors that regulate the expression of IRF6. There are 3 Aims: 1) To generate a mouse model for Van der Woude syndrome by mutating Irf6, and to perform a comprehensive analysis of the pathogenic processes in palate development in these mice. To investigate a role for Type I interferons in palate development in mice, as IRF6 is a member of the Interferon Regulatory family of transcription factors. 2) To evaluate a potential genetic interaction between mutations in Irf6 and Transformation growth factor beta3 (Tgfbeta3), since Tgfa3 is necessary for palate development and for Irf6 expression in the palate. Mice that are double heterozygotes for Irf6 and Tgfbeta3 will be analyzed for palate development. Also, to examine the potential role for Irf6 in transducing the Tgfbeta3 signal during palate development. 3) To identify the enhancer that regulates Irf6 expression in the palate using transgenic mice. Does Tgfbeta3 regulate Irf6 through the SMADs or by other transcription factors or both? Completion of these aims will advance our understanding for the role of IRF6 in palate development, and identify novel gene interactions and genes that may contribute to isolated cleft lip and palate, a common human disorder. This knowledge will provide the basis for enhanced diagnostic tests and future preventive interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013513-05
Application #
7101793
Study Section
Development - 1 Study Section (DEV)
Program Officer
Small, Rochelle K
Project Start
2000-08-01
Project End
2010-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
5
Fiscal Year
2006
Total Cost
$342,081
Indirect Cost
Name
University of Iowa
Department
Pediatrics
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Kousa, Youssef A; Moussa, Dina; Schutte, Brian C (2017) IRF6 expression in basal epithelium partially rescues Irf6 knockout mice. Dev Dyn 246:670-681
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Kousa, Y A; Roushangar, R; Patel, N et al. (2017) IRF6 and SPRY4 Signaling Interact in Periderm Development. J Dent Res 96:1306-1313
Kousa, Youssef A; Schutte, Brian C (2016) Toward an orofacial gene regulatory network. Dev Dyn 245:220-32
Fakhouri, Walid D; Rahimov, Fedik; Attanasio, Catia et al. (2014) An etiologic regulatory mutation in IRF6 with loss- and gain-of-function effects. Hum Mol Genet 23:2711-20
Peyrard-Janvid, Myriam; Leslie, Elizabeth J; Kousa, Youssef A et al. (2014) Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development. Am J Hum Genet 94:23-32
Leslie, Elizabeth J; Mancuso, Jennifer L; Schutte, Brian C et al. (2013) Search for genetic modifiers of IRF6 and genotype-phenotype correlations in Van der Woude and popliteal pterygium syndromes. Am J Med Genet A 161A:2535-2544
Boell, Louis; Pallares, Luisa F; Brodski, Claude et al. (2013) Exploring the effects of gene dosage on mandible shape in mice as a model for studying the genetic basis of natural variation. Dev Genes Evol 223:279-87
Aldhamen, Y A; Seregin, S S; Kousa, Y A et al. (2013) Improved cytotoxic T-lymphocyte immune responses to a tumor antigen by vaccines co-expressing the SLAM-associated adaptor EAT-2. Cancer Gene Ther 20:564-75
de la Garza, Gabriel; Schleiffarth, Jack Robert; Dunnwald, Martine et al. (2013) Interferon regulatory factor 6 promotes differentiation of the periderm by activating expression of Grainyhead-like 3. J Invest Dermatol 133:68-77

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