Intercalated disc protein Xin? is required for Hippo-YAP signaling in the heart.

ABSTRACT: Intercalated discs (ICD), specific cell-to-cell contacts that connect adjacent cardiomyocytes, ensure mechanical and electrochemical coupling during contraction of the heart. Mutations in genes encoding ICD components are linked to cardiovascular diseases. Here, we show that loss of Xin?, a newly-identified component of ICDs, results in cardiomyocyte proliferation defects and cardiomyopathy. We uncovered a role for Xin? in signaling via the Hippo-YAP pathway by recruiting NF2 to the ICD to modulate cardiac function. In Xin? mutant hearts levels of phosphorylated NF2 are substantially reduced, suggesting an impairment of Hippo-YAP signaling. Cardiac-specific overexpression of YAP rescues cardiac defects in Xin? knock-out mice-indicating a functional and genetic interaction between Xin? and YAP. Our study reveals a molecular mechanism by which cardiac-expressed intercalated disc protein Xin? modulates Hippo-YAP signaling to control heart development and cardiac function in a tissue specific manner. Consequently, this pathway may represent a therapeutic target for the treatment of cardiovascular diseases.

SUBMITTER: Guo H 

PROVIDER: S-EPMC7494909 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature