Abstract
The mouse Xin repeat-containing proteins (mXinα and mXinβ) localize to the intercalated disc in the heart. mXinα is able to bundle actin filaments and to interact with β-catenin, suggesting a role in linking the actin cytoskeleton to N-cadherin/β-catenin adhesion. mXinα-null mouse hearts display progressively ultrastructural alterations at the intercalated discs, and develop cardiac hypertrophy and cardiomyopathy with conduction defects. The up-regulation of mXinβ in mXinα-deficient mice suggests a partial compensation for the loss of mXinα. To elucidate the evolutionary relationship between these proteins and to identify the origin of Xin, a phylogenetic analysis was done with 40 vertebrate Xins. Our results show that the ancestral Xin originated prior to the emergence of lamprey and subsequently underwent gene duplication early in the vertebrate lineage. A subsequent teleost-specific genome duplication resulted in most teleosts encoding at least three genes. All Xins contain a highly conserved β-catenin-binding domain within the Xin repeat region. Similar to mouse Xins, chicken, frog and zebrafish Xins also co-localized with β-catenin to structures that appear to be the intercalated disc. A putative DNA-binding domain in the N-terminus of all Xins is strongly conserved, whereas the previously characterized Mena/VASP-binding domain is a derived trait found only in Xinαs from placental mammals. In the C-terminus, Xinαs and Xinβs are more divergent relative to each other but each isoform from mammals shows a high degree of within-isoform sequence identity. This suggests different but conserved functions for mammalian Xinα and Xinβ. Interestingly, the origin of Xin ca. 550 million years ago coincides with the genesis of heart chambers with complete endothelial and myocardial layers. We postulate that the emergence of the Xin paralogs and their functional differentiation may have played a key role in the evolutionary development of the heart.
Highlights
The striated muscle-specific Xin gene was first identified in a differential mRNA display screen in chicken embryos and later shown to be necessary for proper cardiac morphogenesis by Xin antisense experiments [1,2]
Consistent with the presence of the b-catenin-binding domain, immunofluorescence studies revealed co-localization of Xin with b-catenin in chicken, frog and zebrafish hearts. These results suggest that the role of Xin in linking actin with b-catenin through the conserved repeat region is one of the novel innovations that aided in the evolution of a true multi-chambered heart
Origin and evolution of the Xin repeats Searching the genome databases at NCBI, e!Ensembl, Department of Energy Joint Genome Institute (DOE JGI) and Genoscope with the conserved Xin repeat regions of mXina, mXinb, chicken Xin (cXin) and the zebrafish Xins, showed that the lamprey (P. marinus) was the earliest diverging lineage to contain a single copy of the Xinrepeat containing gene
Summary
The striated muscle-specific Xin gene was first identified in a differential mRNA display screen in chicken embryos and later shown to be necessary for proper cardiac morphogenesis by Xin antisense experiments [1,2]. In the N-terminal sequence upstream of the Xin repeats, a Mena/VASP-binding domain in hXina [10] and a putative DNA-binding domain in cXin and mXin [1] have been identified. The b-catenin binding domain is mapped to amino acid residues 535 to 636 of mXina, which overlaps with the actin binding domains; i.e., the Xin repeats [9]. The in vitro actin binding and bundling activities of mXina are significantly enhanced by the presence of b-catenin [9] These results together suggest that through direct interaction, b-catenin likely recruits mXina to the intercalated disc and activates its actin binding and bundling activities. There is an upregulated expression of mXinb at both message and protein levels in mXina-null mouse hearts, suggesting mXinb may be partially compensating for the loss of mXina [5]
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