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Title: sox9b is required in cardiomyocytes for cardiac morphogenesis and function.

Authors: Gawdzik, Joseph C; Yue, Monica S; Martin, Nathan R; Elemans, Loes M H; Lanham, Kevin A; Heideman, Warren; Rezendes, Ryan; Baker, Tracie R; Taylor, Michael R; Plavicki, Jessica S

Published In Sci Rep, (2018 09 17)

Abstract: The high mobility group transcription factor SOX9 is expressed in stem cells, progenitor cells, and differentiated cell-types in developing and mature organs. Exposure to a variety of toxicants including dioxin, di(2-ethylhexyl) phthalate, 6:2 chlorinated polyfluorinated ether sulfonate, and chlorpyrifos results in the downregulation of tetrapod Sox9 and/or zebrafish sox9b. Disruption of Sox9/sox9b function through environmental exposures or genetic mutations produce a wide range of phenotypes and adversely affect organ development and health. We generated a dominant-negative sox9b (dnsox9b) to inhibit sox9b target gene expression and used the Gal4/UAS system to drive dnsox9b specifically in cardiomyocytes. Cardiomyocyte-specific inhibition of sox9b function resulted in a decrease in ventricular cardiomyocytes, an increase in atrial cardiomyocytes, hypoplastic endothelial cushions, and impaired epicardial development, ultimately culminating in heart failure. Cardiomyocyte-specific dnsox9b expression significantly reduced end diastolic volume, which corresponded with a decrease in stroke volume, ejection fraction, and cardiac output. Further analysis of isolated cardiac tissue by RT-qPCR revealed cardiomyocyte-specific inhibition of sox9b function significantly decreased the expression of the critical cardiac development genes nkx2.5, nkx2.7, and myl7, as well as c-fos, an immediate early gene necessary for cardiomyocyte progenitor differentiation. Together our studies indicate sox9b transcriptional regulation is necessary for cardiomyocyte development and function.

PubMed ID: 30224706 Exiting the NIEHS site

MeSH Terms: Animals; Gene Expression Regulation, Developmental; Genes, Dominant; HEK293 Cells; Heart/embryology*; Humans; Mice; Morphogenesis*; Myocytes, Cardiac/metabolism*; SOX9 Transcription Factor/genetics*; SOX9 Transcription Factor/metabolism; Transcription, Genetic; Zebrafish

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