Abstract
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.
Highlights
Proper folding in the endoplasmic reticulum (ER) is a prerequisite for correct localization and function of most secreted and transmembrane proteins[1]
We have previously demonstrated that calmegin (CLGN) and calsperin (CALR3) are testis specific homologues of CANX and CALR, respectively, and are expressed in the ER of spermatogenic cells[4,5,14]
Whereas CALR was dispensable for spermatogenesis and sperm fertilizing ability, it was required in the oocyte for the maturation of the TGF-beta family proteins, GDF9 and BMP15, as well as the subsequent development of the cumulus oocyte complex (COC)
Summary
Proper folding in the endoplasmic reticulum (ER) is a prerequisite for correct localization and function of most secreted and transmembrane proteins[1]. In the ER, soluble calreticulin (CALR) and membrane bound calnexin (CANX) were originally discovered as homologous calcium binding proteins and later shown to be lectin like chaperones that mediate nascent glycoprotein folding[7,8,9]. Despite their extensive homology, CALR and CANX have contrasting functions. Oocytes secrete many factors that regulate the growth and differentiation of granulosa cells, including GDF9 and BMP15 These two proteins are structurally complex with extensive disulfide-bonds and N-linked glycans. Our results highlight the importance of CALR for female reproduction and suggest that compromised CALR function can lead to ovarian insufficiency and female sterility
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