Essential roles of an intercalated disc protein, mXinβ, in postnatal heart growth and survival

RATIONALE: The Xin repeat-containing proteins mXinα and mXinβ localize to the intercalated disc of mouse heart and are implicated in cardiac development and function. The mXinα directly interacts with β-catenin, p120-catenin, and actin filaments. Ablation of mXinα results in adult late-onset cardiomyopathy with conduction defects. An upregulation of the mXinβ in mXinα-deficient hearts suggests a partial compensation. OBJECTIVE: The essential roles of mXinβ in cardiac development and intercalated disc maturation were investigated. METHODS AND RESULTS: Ablation of mXinβ led to abnormal heart shape, ventricular septal defects, severe growth retardation, and postnatal lethality with no upregulation of the mXinα. Postnatal upregulation of mXinβ in wild-type hearts, as well as altered apoptosis and proliferation in mXinβ-null hearts, suggests that mXinβ is required for postnatal heart remodeling. The mXinβ-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 mXinβ resulted in the failure of forming mature intercalated discs and the mislocalization of mXinα and N-cadherin. The mXinβ-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 mXinβ in the intercalated disc maturation but also mechanisms of mXinβ modulating N-cadherin-mediated adhesion signaling and its crosstalk signaling for postnatal heart growth and animal survival.