Congenital diaphragmatic defects are common birth defects with high morbidity and mortality secondary to associated pulmonary hypoplasia. Despite the significant impact that these defects have, the molecular mechanisms underlying their development are not understood. We identified a hypomorphic mutation in the mouse gene, Fog2 that causes a diaphragmatic defect with primary pulmonary hypoplasia and a de novo FOG2 mutation in a baby with a posterior diaphragmatic defect and pulmonary hypoplasia. FOG2 is thus the first gene implicated in the pathogenesis of non-syndromic congenital diaphragmatic defects, and its necessity for pulmonary development validates the hypothesis that neonates with congenital diaphragmatic defects may also have primary pulmonary abnormalities. We found that Fog2 dependent lobar development is mediated by a Fog2-Gata4 interaction. Gata4 is also implicated in diaphragm development in the mouse, and is a candidate gene for human diaphragmatic defects based on its location in a Congenital Diaphragmatic Hernia (CDH) cytogenetic hot spot. The purpose of this proposal is to identify pathway genes and mechanisms of Fog2-Gata4 mediated lung and diaphragm development.
In Specific Aim 1, genes that share expression patterns with Fog2 and Gata4 in the early branching lung will be investigated, and genes will be identified that are modulated by Fog2-Gata4 interactions in the lung at the time of lobar budding.
Specific Aim 2 will evaluate the role of retinoic acid signaling in Fog2 and Fog2-Gata4 mediated development, as retinoic acid plays a role in both diaphragm and lung development, and retinoic acid receptors interact with Fog2.
In Specific Aim 3, it will be determined whether Fog2 and Gata4 are needed in posterior mesenchymal tissue for normal development. Since Fog2 and Gata4 are required for nomal human lung and diaphragm development and both are CDH candidate genes, this proposal will identify the genetic pathways that control this development leading to a better understanding of the pathogenesis of human diaphragmatic defects. Project Narrative - congenital diaphragmatic defects are relatively common birth defects with high rates of mortality and long term morbidity secondary to associated lung development defects. Fog2 and Gata4 are genes that are necessary for normal diaphragm and lung development. In this proposal, we will identify candidate genes for congenital diaphragmatic hernia by investigating the genetic mechanisms of Fog2 and Gata4 mediated diaphragm and lung development in mouse models that have been associated with human diaphragmatic and lung defects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085459-05
Application #
8605209
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
2009-07-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Rochester
Department
Pediatrics
Type
School of Medicine & Dentistry
DUNS #
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Paris, Nicole D; Coles, Garry L; Ackerman, Kate G (2015) Wt1 and ?-catenin cooperatively regulate diaphragm development in the mouse. Dev Biol 407:40-56
Coles, Garry L; Ackerman, Kate G (2013) Kif7 is required for the patterning and differentiation of the diaphragm in a model of syndromic congenital diaphragmatic hernia. Proc Natl Acad Sci U S A 110:E1898-905
Ackerman, Kate G; Vargas, Sara O; Wilson, Jay A et al. (2012) Congenital diaphragmatic defects: proposal for a new classification based on observations in 234 patients. Pediatr Dev Pathol 15:265-74
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Kantarci, Sibel; Ackerman, Kate G; Russell, Meaghan K et al. (2010) Characterization of the chromosome 1q41q42.12 region, and the candidate gene DISP1, in patients with CDH. Am J Med Genet A 152A:2493-504