The Xin repeat-containing protein, mXinΒ, initiates the maturation of the intercalated discs during postnatal heart development

Qinchuan Wang, Jenny Li Chun Lin, Stephen Y. Chan, Jim Jung Ching Lin

Research output: Contribution to journalArticle

Abstract

The intercalated disc (ICD) is a unique structure to the heart and plays vital roles in communication and signaling among cardiomyocytes. ICDs are formed and matured during postnatal development through a profound redistribution of the intercellular junctions, as well as recruitment and assembly of more than 200 proteins at the termini of cardiomyocytes. The molecular mechanism underlying this process is not completely understood. The mouse orthologs (. mXinα and mXinΒ) of human cardiomyopathy-associated (. CMYA)/Xin actin-binding repeat-containing protein (. XIRP) genes (. CMYA1/. XIRP1 and CMYA3/. XIRP2, respectively) encode proteins localized to ICDs. Ablation of mXinα results in adult late-onset cardiomyopathy with conduction defects and up-regulation of mXinΒ. ICD structural defects are found in adult but not juvenile mXinα-null hearts. On the other hand, loss of mXinΒ leads to ICD defects at postnatal day 16.5, a developmental stage when the heart is forming ICDs, suggesting mXinΒ is required for ICD formation. Using quantitative Western blot, we showed in this study that mXinΒ but not mXinα was uniquely up-regulated during the redistribution of intercellular junction from the lateral membrane of cardiomyocytes to their termini. In the absence of mXinΒ, the intercellular junctions failed to be restricted to the termini of the cells, and the onset of such defect correlated with the peak expression of mXinΒ. Immunofluorescence staining and subcellular fractionation showed that mXinΒ preferentially associated with the forming ICDs, further suggesting that mXinΒ functioned locally to promote ICD maturation. In contrast, the spatiotemporal expression profile of mXinα and the lack of more severe ICD defects in mXinα-/-;. mXinΒ-/- double knockout hearts than in mXinΒ-/- hearts suggested that mXinα was not essential for the postnatal formation of ICDs. A two-step model for the development of ICD is proposed where mXinΒ is essential for the redistribution of intercellular junction components from the lateral puncta to the cell termini.

Original languageEnglish (US)
Pages (from-to)264-280
Number of pages17
JournalDevelopmental Biology
Volume374
Issue number2
DOIs
Publication statusPublished - Feb 15 2013
Externally publishedYes

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Keywords

  • Development
  • Intercalated disc
  • Maturation
  • MXinΒ-/- double knockout
  • MXinα-/-;
  • N-cadherin
  • Xin repeat-containing family of proteins

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology
  • Molecular Biology

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