Inhibition of Notch signaling rescues cardiovascular development in Kabuki Syndrome.

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.

journal_name

PLoS Biol

journal_title

PLoS biology

authors

Serrano MLA,Demarest BL,Tone-Pah-Hote T,Tristani-Firouzi M,Yost HJ

doi

10.1371/journal.pbio.3000087

subject

Has Abstract

pub_date

2019-09-03 00:00:00

pages

e3000087

issue

9

eissn

1544-9173

issn

1545-7885

pii

PBIOLOGY-D-18-01227

journal_volume

17

pub_type

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