[Frontiers in Bioscience 17, 2566-2593, June 1, 2012]

Xin proteins and intercalated disc maturation, signaling and diseases

Qinchuan Wang1, Jenny Li-Chun Lin1, Kuo-Ho Wu2, Da-Zhi Wang3, Rebecca S. Reiter1, Haley W. Sinn1, Cheng-I Lin2, Jim Jung-Ching Lin1

1Department of Biology, University of Iowa, Iowa City, IA 52242 USA; 2Institute of Physiology, National Defense Medical Center, Taipei, Taiwan, ROC; 3Department of Cardiology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115 USA


1. Abstract
2. Introduction 2.1. Advances in the anatomy of intercalated disc (ICD)
2.1.1. Area composita (mixed type of junctions) exist in mammalian ICDs
2.1.2. Defective adhering junctions generally lead to gap junction remodeling
2.1.3. Linkers involved in molecular crosstalk among different junctions of ICDs Plakoglobin (g-catenin) Plakophilin 2 (PKP2) p0071 (sometimes referred to as PKP4) p120-catenin ZO-1 (zonula occludens-1)
2.1.4. Transitional junction near ICD
2.2. The involvement of ICD in signaling
2.2.1. N-cadherin/b-catenin signaling in the heart
2.2.2. Wnt/b-catenin signaling in the heart
2.2.3. Interplay between Wnt/b-catenin and adhering junction-mediated signaling
2.2.4. ICD influences ion channel surface expression
2.3. Discovery of Xin repeat-containing and ICD-associated protein family
3. Expression, domain structures and function of Xin
3.1. Xin is a striated muscle-restricted gene and a downstream target of Nkx2.5 .and Mef2
3.2. Two phases of the Xin up-regulation during development correlate with chamber/valve formation and postnatal heart growth
3.3. Xin expression is significantly up-regulated in animal models of cardiac hypertrophy and hypertension
3.4. The origin of Xin coincides with the first appearance of true heart chamber, and mXinb is phylogenetically closer to ancestral Xin protein than mXina
3.5. mXinb messages are preferentially localized to ICDs and enriched in cells of the left ventricle, interventricular septum and apex, particularly concentrated at the base of aorta and pulmonary artery of the heart
3.6. Domain structures of Xin proteins
3.7. ICDs are formed postnatally
3.7.1. Redistribution of junctional components during ICD formation Adherens junctions Desmosomes Gap junctions
3.7.2. Molecular mechanism of ICD formation
3.7.3. Roles of mXinb in ICD formation mXinb is required for ICD formation Potential mechanism by which mXinb mediates ICD formation
3.8. mXin plays important roles in the surface expression of ion channels
4. Xin and cardiac diseases
5. Conclusions and Perspectives
6. Acknowledgement
7. References


Intercalated discs (ICDs) are cardiac-specific structures responsible for mechanical and electrical communication among adjacent cardiomyocytes and are implicated in signal transduction. The striated muscle-specific Xin repeat-containing proteins localize to ICDs and play critical roles in ICD formation and cardiac function. Knocking down the Xin gene in chicken embryos collapses the wall of developing heart chambers and leads to abnormal cardiac morphogenesis. In mammals, a pair of paralogous genes, Xinalpha and Xinbeta exist. Ablation of the mouse Xinalpha (mXinalpha) does not affect heart development. Instead, mXinalpha-deficient mice show adult late-onset cardiac hypertrophy and cardiomyopathy with conduction defects. The mXinalpha-deficient hearts up-regulate mouse Xinbeta (mXinbeta), suggesting a partial compensatory role of mXinbeta. Complete loss of mXinbeta, however, leads to failure of forming ICD, mis-localization of mXinalpha, and early postnatal lethality. In this review, we will briefly discuss recent advances in the anatomy and function of ICDs. We will then review what we know about Xin repeat-containing proteins and how this protein family promotes ICD maturation and stability for normal cardiac function.