RRC ID 49684
Author Sarmah S, Muralidharan P, Marrs JA.
Title Embryonic Ethanol Exposure Dysregulates BMP and Notch Signaling, Leading to Persistent Atrio-Ventricular Valve Defects in Zebrafish.
Journal PLoS One
Abstract Fetal alcohol spectrum disorder (FASD), birth defects associated with ethanol exposure in utero, includes a wide spectrum of congenital heart defects (CHDs), the most prevalent of which are septal and conotruncal defects. Zebrafish FASD model was used to dissect the mechanisms underlying FASD-associated CHDs. Embryonic ethanol exposure (3-24 hours post fertilization) led to defects in atrio-ventricular (AV) valvulogenesis beginning around 37 hpf, a morphogenetic event that arises long after ethanol withdrawal. Valve leaflets of the control embryos comprised two layers of cells confined at the compact atrio-ventricular canal (AVC). Ethanol treated embryos had extended AVC and valve forming cells were found either as rows of cells spanning the AVC or as unorganized clusters near the AV boundary. Ethanol exposure reduced valve precursors at the AVC, but some ventricular cells in ethanol treated embryos exhibited few characteristics of valve precursors. Late staged larvae and juvenile fish exposed to ethanol during embryonic development had faulty AV valves. Examination of AVC morphogenesis regulatory networks revealed that early ethanol exposure disrupted the Bmp signaling gradient in the heart during valve formation. Bmp signaling was prominent at the AVC in controls, but ethanol-exposed embryos displayed active Bmp signaling throughout the ventricle. Ethanol exposure also led to mislocalization of Notch signaling cells in endocardium during AV valve formation. Normally, highly active Notch signaling cells were organized at the AVC. In ethanol-exposed embryos, highly active Notch signaling cells were dispersed throughout the ventricle. At later stages, ethanol-exposed embryos exhibited reduced Wnt/β-catenin activity at the AVC. We conclude that early embryonic ethanol exposure alters Bmp, Notch and other signaling activities during AVC differentiation leading to faulty valve morphogenesis and valve defects persist in juvenile fish.
Volume 11(8)
Pages e0161205
Published 2016-1-1
DOI 10.1371/journal.pone.0161205
PII PONE-D-16-18131
PMID 27556898
PMC PMC4996461
MeSH Animals Biomarkers Bone Morphogenetic Proteins / genetics Bone Morphogenetic Proteins / metabolism* Embryo, Nonmammalian* / drug effects Embryo, Nonmammalian* / metabolism Embryonic Development / drug effects* Embryonic Development / genetics Endocardium / drug effects Endocardium / embryology Endocardium / metabolism Ethanol / adverse effects* Gene Expression Regulation, Developmental Heart Defects, Congenital / etiology* Heart Defects, Congenital / pathology Heart Valves / abnormalities Heart Valves / embryology Heart Valves / metabolism Heart Ventricles / abnormalities Heart Ventricles / embryology Heart Ventricles / metabolism Organogenesis / drug effects Receptors, Notch / genetics Receptors, Notch / metabolism* Signal Transduction / drug effects* Wnt Proteins / metabolism Zebrafish
IF 2.74
Times Cited 12
Zebrafish Tg(6xTcf/LefBS-miniP:d2EGFP)