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- Title
Inhibition of Notch signaling rescues cardiovascular development in Kabuki Syndrome.
- Authors
Serrano, Maria de los Angeles; Demarest, Bradley L.; Tone-Pah-Hote, Tarlynn; Tristani-Firouzi, Martin; Yost, H. Joseph
- Abstract
Kabuki Syndrome patients have a spectrum of congenital disorders, including congenital heart defects, the primary determinant of mortality. Seventy percent of Kabuki Syndrome patients have mutations in the histone methyl-transferase KMT2D. However, the underlying mechanisms that drive these congenital disorders are unknown. Here, we generated and characterized zebrafish kmt2d null mutants that recapitulate the cardinal phenotypic features of Kabuki Syndrome, including microcephaly, palate defects, abnormal ear development, and cardiac defects. The cardiac phenotype consists of a previously unknown vasculogenesis defect that affects endocardium patterning and, consequently, heart ventricle lumen formation. Additionally, zebrafish kmt2d null mutants have angiogenesis defects depicted by abnormal aortic arch development, hyperactive ectopic blood vessel sprouting, and aberrant patterning of the brain vascular plexus. We demonstrate that zebrafish kmt2d null mutants have robust Notch signaling hyperactivation in endocardial and endothelial cells, including increased protein levels of the Notch transcription factor Rbpj. Our zebrafish Kabuki Syndrome model reveals a regulatory link between the Notch pathway and Kmt2d during endothelium and endocardium patterning and shows that pharmacological inhibition of Notch signaling rebalances Rbpj protein levels and rescues the cardiovascular phenotype by enhancing endothelial and endocardial cell proliferation and stabilizing endocardial patterning. Taken together, these findings demonstrate that Kmt2d regulates vasculogenesis and angiogenesis, provide evidence for interactions between Kmt2d and Notch signaling in Kabuki Syndrome, and suggest future directions for clinical research. Kabuki Syndrome (KS) is a human congenital disorder with mutations in KMT2D. Zebrafish kmt2d mutants recapitulate human KS phenotypes, have aberrant Notch pathway signaling, and implicate vasculogenesis as a driver of abnormal cardiac development. Pharmacological inhibition of the Notch pathway rescues vasculogenesis in KS zebrafish, with potential therapeutic implications.
- Subjects
NOTCH genes; CARDIOVASCULAR development; NOTCH signaling pathway; CONGENITAL heart disease; ENDOTHELIUM; HEART ventricles; THORACIC aorta; ENDOTHELIAL cells
- Publication
PLoS Biology, 2019, Vol 17, Issue 8, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3000087