ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration

Aharonov, A.; Shakked, A.; Umansky, K. B.; Savidor, A.; Kain, D.; Lendengolts, D.; Revach, O.-Y.; Morikawa, Y.; Dong, J.; Levin, Y.; Geiger, B.; Martin, J. F.; Tzahor, E.

doi:10.1101/2020.01.07.897199

bioRxiv · 10.1101/2020.01.07.897199

ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration

Aharonov, A.·Shakked, A.·Umansky, K. B.·Savidor, A.·Kain, D.·Lendengolts, D.·Revach, O.-Y.·Morikawa, Y.·Dong, J.·Levin, Y.·Geiger, B.·Martin, J. F.·Tzahor, E.

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Abstract

Cardiomyocyte (CM) loss after injury results in adverse remodelling and fibrosis, which inevitably lead to heart failure. ERBB2-Neuregulin and Hippo-YAP signaling pathways are key mediators of CM proliferation and regeneration, yet the crosstalk between these pathways is unclear. Here, we demonstrate in adult mice that transient over-expression (OE) of activated ERBB2 in CMs promotes cardiac regeneration in a heart failure model. OE CMs present an EMT-like regenerative response manifested by cytoskeletal remodelling, junction dissolution, migration, and ECM turnover. Molecularly, we identified YAP as a critical mediator of ERBB2 signaling. In OE CMs, YAP interacts with nuclear envelope and cytoskeletal components, reflecting the altered mechanic state elicited by ERBB2. Hippo-independent activating phosphorylation on YAP at S352 and S274 were enriched in OE CMs, peaking during metaphase, and viral overexpression of YAP phospho-mutants dampened the proliferative competence of OE CMs. Taken together, we demonstrate a potent ERBB2-mediated YAP mechanosensory signaling, involving EMT-like characteristics, resulting in heart regeneration. HighlightsO_LIERBB2-driven regeneration of scarred hearts recapitulates core-EMT processes C_LIO_LIYAP is activated and required downstream to ERBB2 signaling in CMs C_LIO_LIYAP activity is mechanically driven by cytoskeleton and nuclear envelope remodeling C_LIO_LIYAP S274 and S352 phosphorylation is essential for CM mitosis C_LI

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Aharonov, A., Shakked, A., Umansky, K. B., Savidor, A., Kain, D., Lendengolts, D., Revach, O.-Y., Morikawa, Y., Dong, J., Levin, Y., Geiger, B., Martin, J. F., Tzahor, E.. 2020-01-08. ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration. https://doi.org/10.1101/2020.01.07.897199

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