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Regulated metabolism of Vitamin A by retinol dehydrogenase 10 is critical for embryonic development of the heart
Author(s) -
Sandell Lisa L
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.339.3
Subject(s) - retinoic acid , biology , heart development , phenocopy , microbiology and biotechnology , retinol , embryonic heart , vitamin , genetics , endocrinology , embryonic stem cell , medicine , phenotype , gene
Congenital heart disease is a serious human health issue, affecting as many as 1% of live births. For most cases of cardiac birth defect the cause is unknown, reflecting the limitations of our understanding of which environmental agents, genetic factors, and gene‐environment interactions contribute to cardiac abnormalities. The purpose of the current study is to investigate the mode whereby an embryo converts Vitamin A into the potent morphogen retinoic acid and to understand how disturbances in the production of retinoic acid may contribute to developmental malformations of the heart. Precise regulation of retinoic acid production is critical ‐ either excessive or insufficient levels result in cardiac birth defects ‐ yet very little is known about the mechanism whereby this process is controlled. We have demonstrated that the short chain dehydrogenase/reductase RDH10 is the primary enzyme responsible for the first step of embryonic Vitamin A metabolism. We show that embryos with mutations in Rdh10 have severe cardiac developmental abnormalities, including defects in heart looping, myocardial growth, aorticopulmonary septation and morphogenesis of the atria. Using transgenic reporter mice and RNA in situ hybridization we have determined that the Rdh10 −/− cardiac phenotypes are associated with abnormal expression of Hox family A‐P patterning genes and also with defects in cell adhesion and abnormal distribution of extracellular matrix molecules. Finally, utilizing quantitative reverse transcriptase PCR we have demonstrated that Rdh10 gene transcription is a point for feedback control in regulation of retinoic acid production. These data suggest that Rdh10 may be a candidate gene for association with human cardiac abnormalities. Moreover, the data shed light on the molecular mechanism whereby disruptions in Vitamin A metabolism may contribute to congenital heart disease. Grant Funding Source : NIH‐COBRE