title: Endothelial Jarid2/Jumonji is required for normal cardiac development and proper Notch1 expression.
abstract: Jarid2/Jumonji critically regulates developmental processes including cardiovascular development. Jarid2 knock-out mice exhibit cardiac defects including hypertrabeculation with noncompaction of the ventricular wall. However, molecular mechanisms underlying Jarid2-mediated cardiac development remain unknown. To determine the cardiac lineage-specific roles of Jarid2, we generated myocardial, epicardial, cardiac neural crest, or endothelial conditional Jarid2 knock-out mice using Cre-loxP technology. Only mice with an endothelial deletion of Jarid2 recapitulate phenotypic defects observed in whole body mutants including hypertrabeculation and noncompaction of the ventricle. To identify potential targets of Jarid2, combinatorial approaches using microarray and candidate gene analyses were employed on Jarid2 knock-out embryonic hearts. Whole body or endothelial deletion of Jarid2 leads to increased endocardial Notch1 expression in the developing ventricle, resulting in increased Notch1-dependent signaling to the adjacent myocardium. Using quantitative chromatin immunoprecipitation analysis, Jarid2 was found to occupy a specific region on the endogenous Notch1 locus. We propose that failure to properly regulate Notch signaling in Jarid2 mutants likely leads to the defects in the developing ventricular chamber. The identification of Jarid2 as a potential regulator of Notch1 signaling has broad implications for many cellular processes including development, stem cell maintenance, and tumor formation.
authors.affiliation: Department of Anatomy, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Mysliwiec
authors.forename: Emery H
authors.initials: EH
authors.lastname: Bresnick
authors.forename: Youngsook
authors.initials: Y
authors.lastname: Lee
mesh_terms: D000818:Animals; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D009206:Myocardium / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D063151:Polycomb Repressive Complex 2; D051881:Receptor, Notch1 / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C093650:Jarid2 protein, mouse; D009419:Nerve Tissue Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D063151:Polycomb Repressive Complex 2