Genomes and Genes
MOLECULAR MECHANISMS IN DIABETIC EMBRYOPATHY
Principal Investigator: CLAUDIA T KAPPEN
Abstract: 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.
Funding Period: ----------------2010 - ---------------2011-
more information: NIH RePORT
- Wnt signaling in caudal dysgenesis and diabetic embryopathyGabriela Pavlinkova
Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska, USA
Birth Defects Res A Clin Mol Teratol 82:710-9. 2008..Given that there is also an at least threefold higher risk for heart defects and NTDs, it is important to identify the underlying molecular mechanisms for aberrant embryonic development...
- Transgenic studies on homeobox genes in nervous system development: spina bifida in Isl1 transgenic miceClaudia Kappen
Department of Developmental Biology, Pennington Biomedical Research Center Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70810, USA
Transgenic Res 22:343-58. 2013....
- Responses of the embryonic epigenome to maternal diabetesJ Michael Salbaum
Pennington Biomedical Research Center, Department of Regulation of Gene Expression, Baton Rouge, LA 70808, USA
Birth Defects Res A Clin Mol Teratol 94:770-81. 2012....
- Maternal diet modulates placenta growth and gene expression in a mouse model of diabetic pregnancyClaudia Kappen
Department of Developmental Biology, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, United States of America
PLoS ONE 7:e38445. 2012..These results implicate maternal diet as an important factor in pregnancy complications and suggest that the early phases of placenta development could be a critical time window for developmental origins of adult disease...
- Gene expression in teratogenic exposures: a new approach to understanding individual riskClaudia Kappen
Department of Developmental Biology, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808, United States Electronic address
Reprod Toxicol 45:94-104. 2014..We propose that focus on the variation between exposed individuals could help to discover factors that may play a causative role for abnormal developmental processes that occur with incomplete penetrance. ..
- Altered gene expression and spongiotrophoblast differentiation in placenta from a mouse model of diabetes in pregnancyJ M Salbaum
Laboratory of Regulation of Gene Expression, Pennington Biomedical Research Center, Baton Rouge, LA, USA
Diabetologia 54:1909-20. 2011..g. metabolic syndrome and hypertension. We hypothesised that adverse outcomes from diabetic pregnancies may be linked to compromised placental function, and sought to identify cellular and molecular abnormalities in diabetic placenta...
- Maternal diet modulates the risk for neural tube defects in a mouse model of diabetic pregnancyClaudia Kappen
Department of Developmental Biology, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808, USA
Reprod Toxicol 31:41-9. 2011....
- Neural tube defect genes and maternal diabetes during pregnancyJ Michael Salbaum
Laboratory of Regulation of Gene Expression, 6400 Perkins Road, Baton Rouge, Louisiana 70808, USA
Birth Defects Res A Clin Mol Teratol 88:601-11. 2010..This property is difficult to reconcile with observations of consistently altered gene expression in exposed embryos. We here show that maternal diabetes increases the overall variability of gene expression levels in embryos...
- Identification of regulatory elements in the Isl1 gene locusClaudia Kappen
Pennington Biomedical Research Center, Baton Rouge, LA 71010, USA
Int J Dev Biol 53:935-46. 2009..Embryonic Isl1 expression in several tissues of mesodermal origin is driven by a specific enhancer that is located 3-6kb downstream of the gene...
- Diabetic embryopathy: a role for the epigenome?J Michael Salbaum
Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA
Birth Defects Res A Clin Mol Teratol 91:770-80. 2011..Finally, we outline the challenges in moving from findings that correlate epigenomics to developmental phenotypes to scenarios that establish teratogenic causality...