Project Ill's long-term goal is to learn how sister chromatid cohesion proteins regulate gene expression and development in Drosophila. This addresses the Program's long-term goal of explaining the etiology of Cornelia de Lange syndrome (CdLS). CdLS shows many birth defects, including slow growth, mental deficits and structural defects in limbs and organs. CdLS is caused by mutations in three genes encoding sister chromatid cohesion proteins: NIPBL, Smc1 and Smc3. Smc1 and Smc3 are part of the cohesin complex that glues sister chromatids together, and NIPBL puts cohesin on chromosomes. CdLS mutations weakly reduce cohesion protein activity, and do not cause overt chromosome cohesion defects. Early work in Drosophila showed that cohesin also regulates gene expression. This Program is thus testing the idea that changes in gene expression cause CdLS structural birth defects. The data show that NIPBL and cohesin positively and negatively regulate hundreds of genes in human, mouse, zebrafish and Drosophila. It remains unknown what types of target genes, or what numbers or sizes of gene expression differences cause the developmental defects. It is also unknown if decreased cell proliferation contributes to the slow growth or structural birth defects in CdLS. This question arises from the discovery that cohesin regulates expression of known regulators of growth, cell proliferation and protein synthesis, in human, mouse, zebrafish and Drosophila. Project 111 will address key unanswered questions in two Specific Aims: (1) Effects of NIPBL and cohesin dosage on the dynamics of gene expression during development of larval imaginal discs will be measured genome-wide using microarrays. Combinations of target genes identified by the expression screens will be tested to see if changes in their expression cause developmental defects. (2) Effects of NIPBL and cohesin dosage and nutrtion on cell proliferation and growth in larval tissues, and expression of genes that regulate growrth will be quantified. The potential roles of growth regulators will be tested genetically. Increased knowledge of cohesin's roles in gene expression and development will hopefully lead to better diagnosis and therapy for CdLS.

Public Health Relevance

Cornelia de Lange syndrome (CdLS) is genetic disease that causes slow growth, mental impairment, and abnormalities in the face, arms, hands, gut and heart. This project will use fruit flies as model system to discover how the gene changes in CdLS cause these problems. The information from these studies will help develop better methods for diagnosing and treating CdLS.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1-DSR-N)
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Children's Hospital of Philadelphia
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Zuin, Jessica; Franke, Vedran; van Ijcken, Wilfred F J et al. (2014) A cohesin-independent role for NIPBL at promoters provides insights in CdLS. PLoS Genet 10:e1004153
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