Tokuhiro Keizo, Satouh Yuhkoh, Nozawa Kaori, Isotani Ayako, Fujihara Yoshitaka, Hirashima Yumiko, Matsumura Hiroyuki, Takumi Kazuhiro, Miyano Takashi, Okabe Masaru, Benham Adam M, Ikawa Masahito
Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
Graduate School of medicine, Osaka University, Suita, Osaka, Japan.
Sci Rep. 2015 Sep 21;5:14254. doi: 10.1038/srep14254.
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.
钙连接蛋白（CANX）和钙网蛋白（CALR）伴侣蛋白在内质网中介导新生糖蛋白的折叠。在此我们报告，这些伴侣蛋白在雄性和雌性生育中具有不同作用。Canx基因敲除小鼠生长迟缓但可育。Calr基因敲除小鼠在胚胎发育期间死亡，因此无法确定其对生殖的任何影响。因此，我们分别使用Stra8（雄性条件性敲除，mcKO）和Zp3（雌性条件性敲除，fcKO）启动子驱动的Cre重组酶在雄性和雌性生殖细胞中条件性敲除Calr。Calr mcKO雄性小鼠可育，但尽管交配行为正常，fcKO雌性小鼠却不育。令人惊讶的是，我们发现Calr fcKO雌性小鼠由于立方颗粒细胞增殖缺陷而导致卵泡发生受损和排卵率降低。卵母细胞来源的转化生长因子-β家族蛋白在卵泡发育中起主要作用，分子分析显示，Calr fcKO卵母细胞中GDF9和BMP15的正常加工存在缺陷。这些发现突出了CALR在雌性生殖中的重要性，并证明CALR功能受损会导致卵巢功能不全和女性不孕。
