Signaling Pathways That Underlie Heart Disease

Notch signaling underlies the cardiovascular defects in the zebrafish model for Kabuki Syndrome.

Diseases affecting heart function exact an enormous toll on human health, but many of the genetic and molecular mechanisms underlying heart disease remain unknown. Yost and colleagues discovered novel roles for the same developmental signaling pathway in two seemingly unrelated sources of cardiac dysfunction: adult heart failure and embryonic heart malformation. In their first study, the team found that a unique population of heart muscle cells derived from the embryonic neural crest is necessary for healthy heart function. These cells produce a ligand for the Notch signaling receptor, Jag2b, and the absence of the cell population or the jag2b gene during development results in heart failure in adult fish.

In a second study, they found that in a zebrafish model for Kabuki Syndrome, a congenital heart developmental disorder, Notch signaling is overactive. In a result with exciting implications for human patients, they showed that pharmacological inhibition of Notch signaling could restore normal heart development. Together, these two studies have identified a common mechanism that links diverse forms of heart disease.

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Inhibition of Notch signaling rescues cardiovascular development in Kabuki Syndrome. Serrano MLA, Demarest BL, Tone-Pah-Hote T, Tristani-Firouzi M, Yost HJ. PLoS Biol. 2019 Sep;17(9):e3000087.

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