Rationale: The Xin repeat-containing proteins mXin␣ and mXin␤ localize to the intercalated disc of mouse heart and are implicated in cardiac development and function. The mXin␣ directly interacts with ␤-catenin, p120-catenin, and actin filaments. Ablation of mXin␣ results in adult late-onset cardiomyopathy with conduction defects. An upregulation of the mXin␤ in mXin␣-deficient hearts suggests a partial compensation. Objective: The essential roles of mXin␤ in cardiac development and intercalated disc maturation were investigated. Methods and Results: Ablation of mXin␤ led to abnormal heart shape, ventricular septal defects, severe growth retardation, and postnatal lethality with no upregulation of the mXin␣. Postnatal upregulation of mXin␤ in wild-type hearts, as well as altered apoptosis and proliferation in mXin␤-null hearts, suggests that mXin␤ is required for postnatal heart remodeling. The mXin␤-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 mXin␤ resulted in the failure of forming mature intercalated discs and the mislocalization of mXin␣ and N-cadherin. The mXin␤-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 mXin␤ in the intercalated disc maturation but also mechanisms of mXin␤ modulating N-cadherin-mediated adhesion signaling and its crosstalk signaling for postnatal heart growth and animal survival. (Circ Res. 2010;106:1468-1478.)Key Words: N-cadherin-mediated adhesion signaling Ⅲ Xin repeat-containing protein Ⅲ intercalated disc maturation Ⅲ diastolic dysfunction Ⅲ postnatal heart growth A regulatory network of transcription factors is known to control cardiac morphogenesis. Although the core players in this network are highly conserved, from organisms with simple heart-like cells to those with complex four-chambered hearts, it has been theorized and proven that expansion of this regulatory network by adding new transcription factors is a major force for the heart to evolve new structures. 1,2 However, the addition of new transcription factors can only be a part of the mechanism underlying the formation of complex hearts. The transcription factors must act through their downstream targets, which are directly involved in cardiac morphogenesis, growth and function. However, our inventory of such downstream targets remains incomplete.The Xin repeat-containing proteins from chicken and mouse hearts (cXin and mXin␣, respectively) were first identified as a target of the Nkx2.5-Mef2C pathway. 3,4 Another mouse Xin protein, mXin␤ (or myomaxin), has been subsequently identified as a Mef2A downstream target. 5 Evolutionary studies suggest t...

Mouse Xin-alpha (mXin-alpha) encodes a Xin repeat-containing, actin-binding protein localized to the intercalated disc (ICD). Ablation of mXin-alpha progressively leads to disrupted ICD structure, cardiac hypertrophy and cardiomyopathy with conduction defects during adulthood. Such conduction defects could be due to ICD structural defects and/or cell electrophysiological property changes. Here, we showed that despite the normal ICD structure, juvenile mXina-null cardiomyocytes (from 3~4-week-old mice) exhibited a significant reduction in the transient outward K+ current (ITO), similar to adult mutant cells. Juvenile but not adult mutant cardiomyocytes also had a significant reduction in the delayed rectifier K+ current. In contrast, the mutant adult ventricular myocytes had a significant reduction in the inward rectifier K+ current (IK1) on hyperpolarization. These together could account for the prolongation of action potential duration (APD) and the ease of developing early afterdepolarization observed in juvenile mXinalpha-null cells. Interestingly, juvenile mXin-alpha-null cardiomyocytes had a notable decrease in the amplitude of intracellular Ca2+ transient and no change in the L-type Ca2+ current, suggesting that the prolonged APD did not promote an increase in intracellular Ca2+ for cardiac hypertrophy. Juvenile mXin-alpha-null ventricles had reduced levels of membrane-associated Kv channel interacting protein 2, an auxiliary subunit of ITO, and filamin, an actin cross-linking protein. We further showed that mXin-alpha interacted with both proteins, providing a novel mechanism for ITO surface expression Keywords Developmental Changes; Electrophysiology; KChIP2; transient outward K + current; L-type Ca 2+ current Send correspondence to: Cheng-I Lin, Department of Physiology & Biophysics, National Defense Medical Center, No 161, Minchuan East Rd, Sec. 6, Neihu 114, Taipei, Taiwan, Tel: 886-2-87924854, Fax: 886-2-87924860, bme03@ndmctsgh.edu.tw. NIH Public Access Author ManuscriptFront Biosci (Elite Ed). Author manuscript; available in PMC 2012 February 14. Published in final edited form as:Front Biosci (Elite Ed). ; 3: 1425-1442. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript INTRODUCTIONStriated muscle-specific Xin repeat-containing proteins are downstream targets of transcription factors Nkx2.5 and Mef2, localize to the intercalated disc (ICD) of the heart, and are important in cardiac morphogenesis and function (1-7). In mammals, two families of Xin repeat-containing proteins, Xinα and Xinβ, exist (8). Through alternative splicing of messages, each family of Xin gene encodes at least 2 Xin repeat-containing protein variants (major, mXinα or mXinβ, as well as minor, mXinα-a or mXinβ-a in the mouse) (5,7,9). In addition, a third variant (called Xin C) from Xinα gene has been detected in mouse and human heart, however, this variant, if it exists in vivo, did not contain Xin repeats (9). Loss of both mXinα and mXinα-a in the mouse (referred to mXinα-null mouse) heart result...

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