Calreticulin is required for development of the cumulus oocyte complex and female fertility.
Calreticulin is required for development of the cumulus oocyte complex and female fertility.
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DOI：
10.1038/srep14254
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发表时间：
2015-09-21
影响因子：
4.6
通讯作者：
Ikawa M
中科院分区：
文献类型：
--
作者：
Tokuhiro K;Satouh Y;Nozawa K;Isotani A;Fujihara Y;Hirashima Y;Matsumura H;Takumi K;Miyano T;Okabe M;Benham AM;Ikawa M
钙连接蛋白（CANX）和钙网蛋白（CALR）伴侣介导内质网中的新生糖蛋白折叠。在这里，我们报告说，这些分子伴侣在男性和女性的生育能力有不同的作用。Canx基因敲除小鼠生长迟缓，但能生育。Calr基因敲除小鼠在胚胎发育期间死亡，对生殖产生不确定的影响。因此，我们分别使用Stra 8（mcKO）和Zp 3（fcKO）启动子驱动的Cre重组酶有条件地消融雄性和雌性生殖细胞中的Calr。Calr mcKO雄性小鼠是可育的，但fcKO雌性小鼠尽管有正常的交配行为，但是不育的。引人注目的是，我们发现Calr fcKO雌性小鼠由于立方颗粒细胞的增殖缺陷而导致卵泡发生受损和排卵率降低。卵母细胞衍生的TGF-β家族蛋白在卵泡发育中起主要作用，并且分子分析揭示了GDF 9和BMP 15的正常加工在Calr fcKO卵母细胞中是有缺陷的。这些发现强调了CALR在女性生殖中的重要性，并证明CALR功能受损会导致卵巢功能不全和女性不孕。
Calnexin (CANX) and calreticulin (CALR) chaperones mediate nascent glycoprotein folding in the endoplasmic reticulum. Here we report that these chaperones have distinct roles in male and female fertility. Canx null mice are growth retarded but fertile. Calr null mice die during embryonic development, rendering indeterminate any effect on reproduction. Therefore, we conditionally ablated Calr in male and female germ cells using Stra8 (mcKO) and Zp3 (fcKO) promoter-driven Cre recombinase, respectively. Calr mcKO male mice were fertile, but fcKO female mice were sterile despite normal mating behavior. Strikingly, we found that Calr fcKO female mice had impaired folliculogenesis and decreased ovulatory rates due to defective proliferation of cuboidal granulosa cells. Oocyte-derived, TGF-beta family proteins play a major role in follicular development and molecular analysis revealed that the normal processing of GDF9 and BMP15 was defective in Calr fcKO oocytes. These findings highlight the importance of CALR in female reproduction and demonstrate that compromised CALR function leads to ovarian insufficiency and female infertility.