TMCO1 is essential for ovarian follicle development by regulating ER Ca(2+) store of granulosa cells.
TMCO1 is essential for ovarian follicle development by regulating ER Ca(2+) store of granulosa cells.
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TMCO1 通过调节颗粒细胞的 ER Ca2 储存对卵泡发育至关重要
DOI：
10.1038/s41418-018-0067-x
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发表时间：
2018-09
影响因子：
12.4
通讯作者：
Tang TS
中科院分区：
文献类型：
--
作者：
Sun Z;Zhang H;Wang X;Wang QC;Zhang C;Wang JQ;Wang YH;An CQ;Yang KY;Wang Y;Gao F;Guo C;Tang TS
TMCO 1（transmartane and coiled-coil domains 1）是一种内质网（ER）跨膜蛋白，可主动防止Ca 2+储存过度填充。为了表征其生理功能，我们产生了Tmco 1 −/−敲除（KO）小鼠。除了人类脑面胸（CFT）发育异常谱的主要临床特征外，Tmco 1-/-女性还表现出卵泡逐渐丧失、卵泡发育受损和生育能力低下，其表型类似于女性卵巢早衰（POF）。与TMCO 1作为Ca 2+负荷激活的Ca 2+通道的作用一致，我们在Tmco 1 −/−颗粒细胞（GC）中检测到了超常的Ca 2+信号。有趣的是，虽然自发的Ca 2+振荡模式被改变，ER Ca 2+存储的生发囊泡（GV）阶段的卵母细胞和中期II（MII）逮捕的鸡蛋是正常的Tmco 1消融。结合RNA测序分析，我们还检测到Tmco 1 −/− GC中ER应激介导的凋亡增加和活性氧（ROS）水平升高，表明Tmco 1缺乏时GC功能障碍。综上所述，这些结果表明，TMCO 1是至关重要的卵泡发育和女性生育力，通过维持ER Ca 2+稳态的GC，破坏这会导致ER应激介导的细胞凋亡和增加细胞ROS水平的GC，从而导致受损的卵泡发育。
TMCO1 (transmembrane and coiled-coil domains 1) is an endoplasmic reticulum (ER) transmembrane protein that actively prevents Ca2+ stores from overfilling. To characterize its physiological function(s), we generated Tmco1−/− knockout (KO) mice. In addition to the main clinical features of human cerebrofaciothoracic (CFT) dysplasia spectrum, Tmco1−/− females manifest gradual loss of ovarian follicles, impaired ovarian follicle development, and subfertility with a phenotype analogous to the premature ovarian failure (POF) in women. In line with the role of TMCO1 as a Ca2+ load-activated Ca2+ channel, we have detected a supernormal Ca2+ signaling in Tmco1−/− granulosa cells (GCs). Interestingly, although spontaneous Ca2+ oscillation pattern was altered, ER Ca2+ stores of germinal vesicle (GV) stage oocytes and metaphase II (MII) arrested eggs were normal upon Tmco1 ablation. Combined with RNA-sequencing analysis, we also detected increased ER stress-mediated apoptosis and enhanced reactive oxygen species (ROS) level in Tmco1−/− GCs, indicating the dysfunctions of GCs upon TMCO1 deficiency. Taken together, these results reveal that TMCO1 is essential for ovarian follicle development and female fertility by maintaining ER Ca2+ homeostasis of GCs, disruption of which causes ER stress-mediated apoptosis and increased cellular ROS level in GCs and thus leads to impaired ovarian follicle development.
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