title: Endocardial Brg1 disruption illustrates the developmental origins of semilunar valve disease.
abstract: The formation of intricately organized aortic and pulmonic valves from primitive endocardial cushions of the outflow tract is a remarkable accomplishment of embryonic development. While not always initially pathologic, developmental semilunar valve (SLV) defects, including bicuspid aortic valve, frequently progress to a disease state in adults requiring valve replacement surgery. Disrupted embryonic growth, differentiation, and patterning events that "trigger" SLV disease are coordinated by gene expression changes in endocardial, myocardial, and cushion mesenchymal cells. We explored roles of chromatin regulation in valve gene regulatory networks by conditional inactivation of the Brg1-associated factor (BAF) chromatin remodeling complex in the endocardial lineage. Endocardial Brg1-deficient mouse embryos develop thickened and disorganized SLV cusps that frequently become bicuspid and myxomatous, including in surviving adults. These SLV disease-like phenotypes originate from deficient endocardial-to-mesenchymal transformation (EMT) in the proximal outflow tract (pOFT) cushions. The missing cells are replaced by compensating neural crest or other non-EMT-derived mesenchyme. However, these cells are incompetent to fully pattern the valve interstitium into distinct regions with specialized extracellular matrices. Transcriptomics reveal genes that may promote growth and patterning of SLVs and/or serve as disease-state biomarkers. Mechanistic studies of SLV disease genes should distinguish between disease origins and progression; the latter may reflect secondary responses to a disrupted developmental system.
authors.affiliation: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA; Department of Biology, University of Oregon, Eugene, OR 97403, USA.
authors.forename: Brynn N
authors.initials: BN
authors.lastname: Akerberg
authors.affiliation: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA; Department of Biology, University of Oregon, Eugene, OR 97403, USA.
authors.forename: Maithri L
authors.initials: ML
authors.lastname: Sarangam
authors.affiliation: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA; Department of Biology, University of Oregon, Eugene, OR 97403, USA. Electronic address: kryn@uoregon.edu.
authors.forename: Kryn
authors.initials: K
authors.lastname: Stankunas
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000196:embryology*; D004265:DNA Helicases / Q000502:physiology*; D004195:Disease Models, Animal; D004699:Endocardium / Q000196:embryology*; D005260:Female; D006349:Heart Valve Diseases / Q000209:etiology*; D051379:Mice; D050778:NFATC Transcription Factors / Q000502:physiology; D009687:Nuclear Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; C513194:Smarca4 protein, mouse; D004265:DNA Helicases
keywords: BAF complex; Bicuspid aortic valve; Brg1; Chromatin remodeling; Endocardial cushions; Endocardial-to-mesenchymal transformation; Outflow tract; Semilunar valves; Valve disease