The risk for birth defects is 3 to 10-fold higher in diabetic pregnancy, and congenital malformations are the main cause of mortality and morbidity in infants born to mothers with diabetes. To devise preventive strategies for diabetic embryopathy, it is necessary to understand its etiology and pathogenesis at the molecular level. Our hypothesis is that metabolic imbalance in diabetic pregnancy de-regulates the expression of pancreatic transcription factors in the developing embryo, thus causing diabetic embryopathy. This idea is supported by transgenic paradigms. In mice, transgenes for the pancreatic transcription factor Isl-1 induce phenotypes that resemble human diabetic embryopathy, specifically neural tube and caudal growth defects. In humans, mutant HLXB9, a pancreatic transcription factor downstream of Isl-1, causes sacral agenesis. We have shown that the basis for caudal growth deficiency is a gone dosage-correlated insult to the mesoderm. Our model states that de-regulation of Isl-1 leads to de-regulation of its downstream target genes that, in turn, are the effectors for pathogenesis of the birth defect phenotype. Two key questions arise from our hypothesis: (i) Which factors regulate Isl-1 in the embryo, and how can Isl-1 expression become deregulated in diabetic pregnancy? (ii) Which downstream pathways are altered, and are they also involved in other posterior growth defects? Experimentally, we pursue the following specific aims: (1) To identify the regulatory elements for normal Isl-1 expression in the embryo, and determine how diabetes affects their activity. We have already identified a caudal region-specific enhancer in the Isl-1 locus, which is a candidate control element for de-regulation by metabolic imbalance. The functional role of gene regulatory elements in diabetic embryopathy will be established in murine pregnancies with genetic or experimentally induced diabetes. (2) To identify targets of Isl-1, and to investigate their role in the pathogenesis of caudal growth defects. To recognize Isl-1 targets in our Isl-1 transgenic mouse system, we will use microarray-based gene expression profiling. Preliminary quantitative real-time PCR results implicate the somatostatin and Wnt signaling pathways in Isl-l-induced caudal growth defects. Novel targets, together with the previously identified targets Pbx-1, Punc, and Hlxb9, will be evaluated in genetic models of caudal deficiencies, and progeny of diabetic pregnancies. These experiments will generate new and comprehensive insights into the function of pancreatic transcription factors and their pathogenic potential in metabolic disease and fetal development.

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Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Human Embryology and Development Subcommittee 1 (HED)
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Grave, Gilman D
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University of Nebraska Medical Center
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Salbaum, J Michael; Kruger, Claudia; MacGowan, Jacalyn et al. (2015) Novel Mode of Defective Neural Tube Closure in the Non-Obese Diabetic (NOD) Mouse Strain. Sci Rep 5:16917
Kappen, Claudia; Salbaum, J Michael (2014) Gene expression in teratogenic exposures: a new approach to understanding individual risk. Reprod Toxicol 45:94-104
Herion, Nils J; Salbaum, J Michael; Kappen, Claudia (2014) Traffic jam in the primitive streak: the role of defective mesoderm migration in birth defects. Birth Defects Res A Clin Mol Teratol 100:608-22
Kappen, Claudia (2013) Modeling anterior development in mice: diet as modulator of risk for neural tube defects. Am J Med Genet C Semin Med Genet 163C:333-56
Kappen, Claudia; Yaworsky, Paul J; Muller, Yunhua L et al. (2013) Transgenic studies on homeobox genes in nervous system development: spina bifida in Isl1 transgenic mice. Transgenic Res 22:343-58
Kappen, Claudia; Kruger, Claudia; MacGowan, Jacalyn et al. (2012) Maternal diet modulates placenta growth and gene expression in a mouse model of diabetic pregnancy. PLoS One 7:e38445
Molloy, Anne M; Kappen, Claudia (2012) Papers from the 7th International Neural Tube Defects Conference. Birth Defects Res A Clin Mol Teratol 94:747-8
Salbaum, J Michael; Kappen, Claudia (2012) Responses of the embryonic epigenome to maternal diabetes. Birth Defects Res A Clin Mol Teratol 94:770-81
Salbaum, J M; Kruger, C; Zhang, X et al. (2011) Altered gene expression and spongiotrophoblast differentiation in placenta from a mouse model of diabetes in pregnancy. Diabetologia 54:1909-20
Salbaum, J Michael; Kappen, Claudia (2011) Diabetic embryopathy: a role for the epigenome? Birth Defects Res A Clin Mol Teratol 91:770-80

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