Abstract
BackgroundWe have reported previously that when chromosome Y (chrY) from the mouse strain C57BL/6J (ChrYC57) was substituted for that of A/J mice (ChrYA), cardiomyocytes from the resulting "chromosome substitution" C57BL/6J-chrYA strain were smaller than that of their C57BL/6J counterparts. In reverse, when chrYA from A/J mice was substituted for that of chrYC57, cardiomyocytes from the resulting A/J-chrYC57 strain were larger than in their A/J counterparts. We further used these strains to test whether: 1) the origin of chrY could also be linked to differences in the profile of gene expression in the hearts of adult male mice, and 2) post-pubertal testosterone could play a role in the differential morphologic and/or molecular effects of chrYC57 and chrYA.ResultsThe increased size of cardiomyocytes from adult male C57BL/6J mice compared to C57BL/6J-chrYA resulted from the absence of hypertrophic effects of post-pubertal testosterone on cells from the latter strain. However, gene profiling revealed that the latter effect could not be explained on the basis of an insensitivity of cells from C57BL/6J-chrYA to androgens, since even more cardiac genes were affected by post-pubertal testosterone in C57BL/6J-chrYA hearts than in C57BL/6J. By testing for interaction between the effects of surgery and strain, we identified 249 "interaction genes" whose expression was affected by post-pubertal testosterone differentially according to the genetic origin of chrY. These interaction genes were found to be enriched within a limited number of signaling pathways, including: 1) p53 signaling, which comprises the interacting genes Ccnd1, Pten and Cdkn1a that are also potential co-regulators of the androgen receptors, and 2) circadian rhythm, which comprises Arntl/Bmal1, which may in turn regulate cell growth via the control of Cdkn1a.ConclusionAlthough post-pubertal testosterone increased the size of cardiomyocytes from male C56BL/6J mice but not that from their C57BL/6J-chrYA counterparts, it affected gene expression in the hearts from both strains. However, several cardiac genes responded to post-pubertal testosterone in a strict strain-selective manner, which provides possible mechanisms explaining how chrY may, in part via interference with androgen regulatory events, be linked to morphologic differences of cardiac cells of adult male mice.
Highlights
We have reported previously that when chromosome Y from the mouse strain C57BL/6J (ChrYC57) was substituted for that of A/J mice (ChrYA), cardiomyocytes from the resulting "chromosome substitution" C57BL/6J-chrYA strain were smaller than that of their C57BL/6J counterparts
In agreement with the linkage mapping results, we found that when Chromosome Y (chrY) from the parental strain C57BL/6J (ChrYC57) was substituted for that of A/J mice (ChrYA), CMs from the resulting "chromosome substitution" C57BL/6J-chrYA strain (C57.YA) were smaller than that of their C57BL/6J counterparts
In extension to our previous findings showing that CMs from strains carrying chrYC57 were larger than that from their counterparts carrying chrYA [11], we found that prepubertal castration decreased the size of CMs in adult animals from strains carrying YC57 (i.e. C57BL/6J and A.YC57 mice), but not in their counterparts carrying chrY from A/J (YA), i.e. A/J and C57.YA mice (Figure 1)
Summary
We have reported previously that when chromosome Y (chrY) from the mouse strain C57BL/6J (ChrYC57) was substituted for that of A/J mice (ChrYA), cardiomyocytes from the resulting "chromosome substitution" C57BL/6J-chrYA strain were smaller than that of their C57BL/6J counterparts. In reverse, when chrYA from A/J mice was substituted for that of chrYC57, cardiomyocytes from the resulting A/J-chrYC57 strain were larger than in their A/J counterparts We further used these strains to test whether: 1) the origin of chrY could be linked to differences in the profile of gene expression in the hearts of adult male mice, and 2) post-pubertal testosterone could play a role in the differential morphologic and/or molecular effects of chrYC57 and chrYA. Genetic variants of chrY have been shown to have an impact on functions unrelated to male reproductive biology, including the severity of experimental allergic encephalomyelitis in mice [5], the incidence of prostate cancer in humans [6,7], and several cardiovascular conditions such as hypertension and high plasma cholesterol in either humans or animal models [8,9,10] The mechanism explaining these particular effects of chrY genes are still unclear, and cannot be explored by using classical genetic methods because chrY genes do not recombine. Since: 1) one of the most obvious consequences of chrY is to foster the development of male gonads and the production of testosterone, and 2) there is preliminary evidence that chrY polymorphisms may interfere with some biologic effects of testosterone [10,12], we tested whether postpubertal testosterone could play a role in the differential morphologic and/or molecular effects of chrYC57 and chrYA on cardiac cells
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