Deletion of Gas2l3 in mice leads to specific defects in cardiomyocyte cytokinesis during development

Mammalian cardiomyocytes lose the ability to proliferate shortly after birth. This accounts for the limited regeneration capacity of the mammalian heart. A characteristic feature of growth arrested cardiomyocytes is binucleation, but the molecular mechanisms are not well understood. In rodents, binucleation of cardiomyocytes starts after birth and occurs through incomplete cytokinesis. Here we demonstrate an important and unexpected role of GAS2L3, a recently identified actin and tubulin binding protein, for cardiomyocyte cytokinesis during heart development in mice. Mice deficient in GAS2L3 die shortly after birth due to dilated cardiomyopathy. Cardiomyocyte-specific deletion of GAS2L3 confirmed that the phenotype resulted from the loss of GAS2L3 in cardiomyocytes. We show that a deficiency in GAS2L3 leads to a strong reduction in cardiomyocyte numbers due to reduced proliferation. In addition, the loss of Gas2l3 resulted in premature binucleation of cardiomyocytes and in induction of a p53-transcriptional program including the cell cycle inhibitor p21. Collectively, these data identify an important role for GAS2L3 in cardiomyocyte cytokinesis during development. Sequencing of mRNA extracted from hearts of E18.5 wildtype and Gas2L3 -/- mouse embryos , in triplicate, using Illumina NextSeq500.哺乳动物心肌细胞在出生后短期内便丧失增殖能力，这正是哺乳动物心脏再生能力有限的核心原因。生长停滞的心肌细胞的典型特征为双核化，但目前对其背后的分子机制尚不完全明确。在啮齿类动物中，心肌细胞的双核化始于出生后，且通过不完全胞质分裂完成。本研究证实，新近鉴定的肌动蛋白与微管蛋白结合蛋白GAS2L3在小鼠心脏发育过程中，对心肌细胞胞质分裂发挥着重要且出人意料的作用。GAS2L3缺陷小鼠会因扩张型心肌病在出生后短期内死亡。通过心肌细胞特异性敲除GAS2L3，证实该表型正是由心肌细胞内GAS2L3的缺失所导致。研究发现，GAS2L3缺失会因增殖能力下降导致心肌细胞数量显著减少。此外，Gas2l3的缺失会促使心肌细胞提前发生双核化，并诱导包括细胞周期抑制剂p21在内的p53转录程序激活。综上，本研究数据证实GAS2L3在发育过程中心肌细胞胞质分裂中发挥重要作用。采用Illumina NextSeq500平台，对分别提取自E18.5（胚胎发育第18.5天）野生型与Gas2l3基因敲除小鼠胚胎心脏的mRNA进行三次重复测序。