title: Calreticulin is required for development of the cumulus oocyte complex and female fertility.
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.
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Tokuhiro
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Yuhkoh
authors.initials: Y
authors.lastname: Satouh
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.|Graduate School of medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Nozawa
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.|Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.|Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Isotani
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Fujihara
authors.affiliation: Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Hirashima
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.|Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Matsumura
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.|Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takumi
authors.affiliation: Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyano
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Okabe
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.|School of Biological and Biomedical Sciences, Durham University, Durham, United Kingdom.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Benham
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.|Graduate School of medicine, Osaka University, Suita, Osaka, Japan.|Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.|Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Ikawa
mesh_terms: D000818:Animals; D055430:Bone Morphogenetic Protein 15 / Q000378:metabolism; D037281:Calnexin / Q000235:genetics* / Q000378:metabolism; D037282:Calreticulin / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D054885:Cumulus Cells / Q000166:cytology / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D005298:Fertility / Q000502:physiology; D055429:Growth Differentiation Factor 9 / Q000378:metabolism; D007247:Infertility, Female / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009865:Oocytes / Q000166:cytology / Q000254:growth & development; D009924:Organ Culture Techniques; D006080:Ovarian Follicle / Q000166:cytology / Q000196:embryology*; D010060:Ovulation / Q000235:genetics; D016649:Primary Ovarian Insufficiency / Q000235:genetics; D017510:Protein Folding; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C525902:Bmp15 protein, mouse; D055430:Bone Morphogenetic Protein 15; D037282:Calreticulin; C525898:Gdf9 protein, mouse; D055429:Growth Differentiation Factor 9; D016212:Transforming Growth Factor beta; D037281:Calnexin