Abstract
Most mouse cardiomyocytes (CMs) become multinucleated shortly after birth via endoreplication and interrupted mitosis, which persists through adulthood. The very closely related inbred mouse strains BALB/cJ and BALB/cByJ differ substantially (6.6% vs. 14.3%) in adult mononuclear CM level. This difference is the likely outcome of a single X-linked polymorphic gene that functions in a CM-nonautonomous manner, and for which the BALB/cByJ allele is recessive to that of BALB/cJ. From whole exome sequence we identified two new X-linked protein coding variants that arose de novo in BALB/cByJ, in the genes Gdi1 (R276C) and Irs4 (L683F), but show that neither affects mononuclear CM level individually. No BALB/cJ-specific X-linked protein coding variants were found, implicating instead a variant that influences gene expression rather than encoded protein function. A substantially higher percentage of mononuclear CMs in BALB/cByJ are tetraploid (66.7% vs. 37.6% in BALB/cJ), such that the overall level of mononuclear diploid CMs between the two strains is similar. The difference in nuclear ploidy is the likely result of an autosomal polymorphism, for which the BALB/cByJ allele is recessive to that of BALB/cJ. The X-linked and autosomal genes independently influence mitosis such that their phenotypic consequences can be combined or segregated by appropriate breeding, implying distinct functions in karyokinesis and cytokinesis.
Highlights
Www.nature.com/scientificreports polyploid CMs include regenerative capacity, sensitivity to oxidative stress, contractility, gene expression, metabolism, and others[1,2]
We first addressed whether the striking difference in mononuclear CM content between BALB/cJ and BALB/cByJ adult females was true in males
The polyploid nature of almost all adult cardiomyocytes in human, mouse, rat, and several other species has been known for decades, and yet the mechanisms that account for this outcome have remained obscure
Summary
Www.nature.com/scientificreports polyploid CMs include regenerative capacity, sensitivity to oxidative stress, contractility, gene expression, metabolism, and others[1,2]. Most polyploid CMs are binucleated with two diploid nuclei (2 × 2n) In this prior analysis, we first surveyed a large number of inbred mouse strains for the percentage of mononuclear CMs, and measured nuclear ploidy within the mononuclear CM subset only for selected strains. As a demonstration of this principle, by genome-wide association we identified a natural loss-of-function variant in the gene Tnni3k in many inbred strains that have a high level of mononuclear CMs, and confirmed in a controlled C57BL/6J strain background (which normally carries the functional wild-type Tnni3k allele) that mutation of this gene resulted in a 2–3-fold increase in the percentage of adult mononuclear CMs and in the percentage of diploid CMs9,10. The goal of this study was to explore the genetic basis of the divergence in CM composition between BALB/ cJ and BALB/cByJ, and the implications of this divergence for the general subject of diploid and polyploid CMs in mice
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