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PMID:23918388

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Citation

Xin, M, Kim, Y, Sutherland, LB, Murakami, M, Qi, X, McAnally, J, Porrello, ER, Mahmoud, AI, Tan, W, Shelton, JM, Richardson, JA, Sadek, HA, Bassel-Duby, R and Olson, EN (2013) Hippo pathway effector Yap promotes cardiac regeneration. Proc. Natl. Acad. Sci. U.S.A. 110:13839-44

Abstract

The adult mammalian heart has limited potential for regeneration. Thus, after injury, cardiomyocytes are permanently lost, and contractility is diminished. In contrast, the neonatal heart can regenerate owing to sustained cardiomyocyte proliferation. Identification of critical regulators of cardiomyocyte proliferation and quiescence represents an important step toward potential regenerative therapies. Yes-associated protein (Yap), a transcriptional cofactor in the Hippo signaling pathway, promotes proliferation of embryonic cardiomyocytes by activating the insulin-like growth factor and Wnt signaling pathways. Here we report that mice bearing mutant alleles of Yap and its paralog WW domain containing transcription regulator 1 (Taz) exhibit gene dosage-dependent cardiac phenotypes, suggesting redundant roles of these Hippo pathway effectors in establishing proper myocyte number and maintaining cardiac function. Cardiac-specific deletion of Yap impedes neonatal heart regeneration, resulting in a default fibrotic response. Conversely, forced expression of a constitutively active form of Yap in the adult heart stimulates cardiac regeneration and improves contractility after myocardial infarction. The regenerative activity of Yap is correlated with its activation of embryonic and proliferative gene programs in cardiomyocytes. These findings identify Yap as an important regulator of cardiac regeneration and provide an experimental entry point to enhance this process.

Links

PubMed PMC3752208 Online version:10.1073/pnas.1313192110

Keywords

Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Animals; Blotting, Western; DNA Primers/genetics; Echocardiography; Heart/physiology; Histological Techniques; Mice; Mice, Transgenic; Mutation, Missense/genetics; Myocardial Contraction/genetics; Myocardial Contraction/physiology; Myocytes, Cardiac/metabolism; Myocytes, Cardiac/physiology; Phosphoproteins/genetics; Phosphoproteins/metabolism; Protein-Serine-Threonine Kinases/metabolism; Regeneration/physiology; Signal Transduction/physiology; Tetrazolium Salts; Transcription Factors/genetics; Transcription Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:YAP1

involved_in

GO:0001894: tissue homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:YAP1

involved_in

GO:0003015: heart process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:YAP1

involved_in

GO:0061026: cardiac muscle tissue regeneration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • happens_during:(UBERON:0007221)|part_of(GO:0002931)

Seeded From UniProt

complete

MOUSE:YAP1

involved_in

GO:0060045: positive regulation of cardiac muscle cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:YAP1

involved_in

GO:0042060: wound healing

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • happens_during:(UBERON:0007221)|part_of(GO:0002931)

Seeded From UniProt

complete

MOUSE:WWTR1

involved_in

GO:0003015: heart process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:WWTR1

involved_in

GO:0001894: tissue homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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