Dystrophin-glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation

被引:228
作者
Morikawa, Yuka [1 ]
Heallen, Todd [1 ]
Each, John L. [2 ]
Xiao, Yang [1 ]
Martin, James F. [1 ,2 ,3 ,4 ]
机构
[1] Texas Heart Inst, Cardiomyocyte Renewal Lab, Houston, TX 77030 USA
[2] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA
[3] Baylor Coll Med, Program Dev Biol, Houston, TX 77030 USA
[4] Baylor Coll Med, Houston, TX 77030 USA
基金
美国国家卫生研究院;
关键词
DUCHENNE MUSCULAR-DYSTROPHY; ADULT HEART REGENERATION; IN-VIVO; PRESSURE-OVERLOAD; MOUSE MODEL; MUSCLE; GENE; MICE;
D O I
10.1038/nature22979
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The regenerative capacity of the adult mammalian heart is limited, because of the reduced ability of cardiomyocytes to progress through mitosis(1). Endogenous cardiomyocytes have regenerative capacity at birth but this capacity is lost postnatally, with subsequent organ growth occurring through cardiomyocyte hypertrophy(2,3). 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(4,5). The dystrophingly-coprotein 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.
引用
收藏
页码:227 / +
页数:17
相关论文
共 21 条
[1]   No Evidence for Cardiomyocyte Number Expansion in Preadolescent Mice [J].
Alkass, Kanar ;
Panula, Joni ;
Westman, Mattias ;
Wu, Ting-Di ;
Guerquin-Kern, Jean-Luc ;
Bergmann, Olaf .
CELL, 2015, 163 (04) :1026-1036
[2]   Dynamics of Cell Generation and Turnover in the Human Heart [J].
Bergmann, Olaf ;
Zdunek, Sofia ;
Felker, Anastasia ;
Salehpour, Mehran ;
Alkass, Kanar ;
Bernard, Samuel ;
Sjostrom, Staffan L. ;
Szewczykowska, Mirosawa ;
Jackowska, Teresa ;
dos Remedios, Cris ;
Malm, Torsten ;
Andrae, Michaela ;
Jashari, Ramadan ;
Nyengaard, Jens R. ;
Possnert, Goran ;
Jovinge, Stefan ;
Druid, Henrik ;
Frisen, Jonas .
CELL, 2015, 161 (07) :1566-1575
[3]   Contribution of the different modules in the utrophin carboxy-terminal region to the formation and regulation of the DAP complex [J].
di Vignano, AT ;
Di Zenzo, G ;
Sudol, M ;
Cesareni, G ;
Dente, L .
FEBS LETTERS, 2000, 471 (2-3) :229-234
[4]   Transduction of mechanical and cytoskeletal cues by YAP and TAZ [J].
Halder, Georg ;
Dupont, Sirio ;
Piccolo, Stefano .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2012, 13 (09) :591-600
[5]   Hippo signaling impedes adult heart regeneration [J].
Heallen, Todd ;
Morikawa, Yuka ;
Leach, John ;
Tao, Ge ;
Willerson, James T. ;
Johnson, Randy L. ;
Martin, James F. .
DEVELOPMENT, 2013, 140 (23) :4683-+
[6]   Hippo Pathway Inhibits Wnt Signaling to Restrain Cardiomyocyte Proliferation and Heart Size [J].
Heallen, Todd ;
Zhang, Min ;
Wang, Jun ;
Bonilla-Claudio, Margarita ;
Klysik, Ela ;
Johnson, Randy L. ;
Martin, James F. .
SCIENCE, 2011, 332 (6028) :458-461
[7]   Combined effects of microtopography and cyclic strain on vascular smooth muscle cell orientation [J].
Houtchens, Graham R. ;
Foster, Michael D. ;
Desai, Tejal A. ;
Morgan, Elise F. ;
Wong, Joyce Y. .
JOURNAL OF BIOMECHANICS, 2008, 41 (04) :762-769
[8]   Dystrophin-deficient myocardium is vulnerable to pressure overload in vivo [J].
Kamogawa, Y ;
Biro, S ;
Maeda, M ;
Setoguchi, M ;
Hirakawa, T ;
Yoshida, H ;
Tei, C .
CARDIOVASCULAR RESEARCH, 2001, 50 (03) :509-515
[9]   Combination of tumor necrosis factor-α ablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase-3 knock-out mice [J].
Kassiri, Z ;
Oudit, GY ;
Sanchez, O ;
Dawood, F ;
Mohammed, FF ;
Nuttall, RK ;
Edwards, DR ;
Liu, PP ;
Backx, PH ;
Khokha, R .
CIRCULATION RESEARCH, 2005, 97 (04) :380-390
[10]   Alpha-Catenins Control Cardiomyocyte Proliferation by Regulating Yap Activity [J].
Li, Jifen ;
Gao, Erhe ;
Vite, Alexia ;
Yi, Roslyn ;
Gomez, Ludovic ;
Goossens, Steven ;
van Roy, Frans ;
Radice, Glenn L. .
CIRCULATION RESEARCH, 2015, 116 (01) :70-U172