Dystrophin-glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation. Nature 2017 Jul 13;547(7662):227-231
Date
06/06/2017Pubmed ID
28581498Pubmed Central ID
PMC5528853DOI
10.1038/nature22979Scopus ID
2-s2.0-85024396048 (requires institutional sign-in at Scopus site) 250 CitationsAbstract
The regenerative capacity of the adult mammalian heart is limited, because of the reduced ability of cardiomyocytes to progress through mitosis. Endogenous cardiomyocytes have regenerative capacity at birth but this capacity is lost postnatally, with subsequent organ growth occurring through cardiomyocyte hypertrophy. The Hippo pathway, a conserved kinase cascade, inhibits cardiomyocyte proliferation in the developing heart to control heart size and prevents regeneration in the adult heart. The dystrophin-glycoprotein complex (DGC), a multicomponent transmembrane complex linking the actin cytoskeleton to extracellular matrix, is essential for cardiomyocyte homeostasis. DGC deficiency in humans results in muscular dystrophy, including the lethal Duchenne muscular dystrophy. Here we show that the DGC component dystroglycan 1 (Dag1) directly binds to the Hippo pathway effector Yap to inhibit cardiomyocyte proliferation in mice. The Yap-Dag1 interaction was enhanced by Hippo-induced Yap phosphorylation, revealing a connection between Hippo pathway function and the DGC. After injury, Hippo-deficient postnatal mouse hearts maintained organ size control by repairing the defect with correct dimensions, whereas postnatal hearts deficient in both Hippo and the DGC showed cardiomyocyte overproliferation at the injury site. In the hearts of mature Mdx mice (which have a point mutation in Dmd)-a model of Duchenne muscular dystrophy-Hippo deficiency protected against overload-induced heart failure.
Author List
Morikawa Y, Heallen T, Leach J, Xiao Y, Martin JFAuthor
Yang Xiao Assistant Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAnimals
Cardiomyopathies
Cell Cycle Proteins
Cell Proliferation
Dystroglycans
Dystrophin
Glycoproteins
Heart Failure
Male
Mice
Mice, Inbred C57BL
Mice, Inbred mdx
Multiprotein Complexes
Muscular Dystrophy, Duchenne
Myocytes, Cardiac
Organ Size
Phosphoproteins
Phosphorylation
Pressure
Protein Binding
