Extraembryonic but not embryonic SUMO-specific protease 2 is required for heart development.
Extraembryonic but not embryonic SUMO-specific protease 2 is required for heart development.
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DOI：
10.1038/srep20999
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发表时间：
2016-02-17
影响因子：
4.6
通讯作者：
Hsu W
中科院分区：
文献类型：
--
作者：
Maruyama EO;Lin H;Chiu SY;Yu HM;Porter GA;Hsu W
SUMO特异性蛋白酶2 （SENP2）能够将SUMO从其底物中去除，这对于滋养细胞干细胞、壁龛和谱系的发育至关重要。SENP2的整体缺失导致妊娠中期死亡，并导致胎盘严重缺陷，并伴有胚胎大脑和心脏异常。由于胎盘缺乏，SENP2在胚胎组织发育中的作用尚未得到适当的确定。大脑和心脏的异常可能继发于胎盘功能不全。在这里，我们已经创建了一个新的小鼠品系，允许条件失活SENP2。条件等位基因纯合子的种系缺失小鼠表现出滋养细胞缺陷和胚胎异常，类似于全局SENP2基因敲除。然而，SENP2的组织特异性破坏证明了它在胚胎发生中不可或缺的作用。胎盘表达SENP2是胚胎心脏和大脑发育的必要和充分条件。利用蛋白酶缺陷模型，我们进一步证明了在所有主要滋养细胞谱系的发育中都需要依赖senp2的SUMO修饰。SENP2调节Mdm2的summoylation， Mdm2控制p53的活性，而p53的活性分别对滋养细胞增殖和分化中有丝分裂的G-S过渡和内复制至关重要。滋养层细胞的分化也依赖于senp2介导的p57Kip2的激活，p57Kip2是一种cdk特异性抑制剂，是内复制所必需的。
SUMO-specific protease 2 (SENP2) activities to remove SUMO from its substrates is essential for development of trophoblast stem cells, niches and lineages. Global deletion of SENP2 leads to midgestation lethality, and causes severe defects in the placenta which is accompanied by embryonic brain and heart abnormalities. Because of the placental deficiencies, the role of SENP2 in development of the embryonic tissues has not been properly determined. The brain and heart abnormalities may be secondary to placental insufficiency. Here we have created a new mouse strain permitting conditional inactivation of SENP2. Mice homozygous for germline deletion of the conditional allele exhibit trophoblast defects and embryonic abnormalities resembling the global SENP2 knockout. However, tissue-specific disruptions of SENP2 demonstrate its dispensable role in embryogenesis. Placental expression of SENP2 is necessary and sufficient for embryonic heart and brain development. Using a protease deficient model, we further demonstrate the requirement of SENP2-dependent SUMO modification in development of all major trophoblast lineages. SENP2 regulates sumoylation of Mdm2 which controls p53 activities critical for G-S transition of mitotic division and endoreduplication in trophoblast proliferation and differentiation, respectively. The differentiation of trophoblasts is also dependent on SENP2-mediated activation of p57Kip2, a CDK-specific inhibitor required for endoreduplication.