Rbpms2 prevents major cardiac defects in cardiomyocyte-specific Rbpms-deficient mice

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Cell type-specific splicing depends on RNA-binding splicing factors. Several important splicing factors were identified in cardiomyocytes, including members of the RBPMS family, but their role during heart development has not been fully characterized. Here, we demonstrate that the function of RBPMS overlaps with the closely related paralogue RBPMS2. Rbpms-deficient cardiomyocytes exhibit a higher degree of binucleation but this does not impair heart function in mice within the first year after birth. In contrast, Rbpms/Rbpms2 (Rbpms/2) compound mutants show a pronounced disruption of the splicing network in embryonic cardiomyocytes, which lead to formation of defective nuclei and disruption of sarcomere structures, eventually resulting in embryonic lethality. We demonstrate that mitotic defects in embryonic Rbpms/2-deficient cardiomyoctes are caused by the disbalance of nuclear and cytoplasmic Camk2g isoforms. Overexpression of the Rbpmsa isoform partially rescues these defects, preventing embryonic lethality of Rbpms/2-deficient mice, and is sufficient for cardiomyocyte-specific splicing in other cell types. The file contains images of non-processed blots for the western blot analysis.

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