Essential roles of an intercalated disc protein, mXinbeta, in postnatal heart growth and survival.
BACKGROUND
The Xin repeat-containing proteins mXinalpha and mXinbeta localize to the intercalated disc of mouse heart and are implicated in cardiac development and function. The mXinalpha directly interacts with beta-catenin, p120-catenin, and actin filaments. Ablation of mXinalpha results in adult late-onset cardiomyopathy with conduction defects. An upregulation of the mXinbeta in mXinalpha-deficient hearts suggests a partial compensation.


OBJECTIVE
The essential roles of mXinbeta in cardiac development and intercalated disc maturation were investigated.


RESULTS
Ablation of mXinbeta led to abnormal heart shape, ventricular septal defects, severe growth retardation, and postnatal lethality with no upregulation of the mXinalpha. Postnatal upregulation of mXinbeta in wild-type hearts, as well as altered apoptosis and proliferation in mXinbeta-null hearts, suggests that mXinbeta is required for postnatal heart remodeling. The mXinbeta-null hearts exhibited a misorganized myocardium as detected by histological and electron microscopic studies and an impaired diastolic function, as suggested by echocardiography and a delay in switching off the slow skeletal troponin I. Loss of mXinbeta resulted in the failure of forming mature intercalated discs and the mislocalization of mXinalpha and N-cadherin. The mXinbeta-null hearts showed upregulation of active Stat3 (signal transducer and activator of transcription 3) and downregulation of the activities of Rac1, insulin-like growth factor 1 receptor, protein kinase B, and extracellular signal-regulated kinases 1 and 2.


CONCLUSIONS
These findings identify not only an essential role of mXinbeta in the intercalated disc maturation but also mechanisms of mXinbeta modulating N-cadherin-mediated adhesion signaling and its crosstalk signaling for postnatal heart growth and animal survival.
Wang
Qinchuan
Q
Department of Biology, University of Iowa, Iowa City, IA 52242-1324, USA.
Lin
Jenny Li-Chun
JL
Reinking
Benjamin E
BE
Feng
Han-Zhong
HZ
Chan
Fu-Chi
FC
Lin
Cheng-I
CI
Jin
Jian-Ping
JP
Gustafson-Wagner
Elisabeth A
EA
Scholz
Thomas D
TD
Yang
Baoli
B
Lin
Jim Jung-Ching
JJ
D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D002470:Cell Survival; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D006321:Heart / Q000254:growth & development* / Q000503:physiopathology*; D060588:LIM Domain Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*
D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D009687:Nuclear Proteins; C500305:XIRP2 protein, mouse