Calreticulin is required for development of the cumulus oocyte complex and female fertility

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 15 / metabolism
  • Calnexin / genetics*
  • Calnexin / metabolism
  • Calreticulin / genetics*
  • Calreticulin / metabolism
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Cumulus Cells / cytology
  • Cumulus Cells / metabolism*
  • Endoplasmic Reticulum / metabolism
  • Female
  • Fertility / physiology
  • Growth Differentiation Factor 9 / metabolism
  • Infertility, Female / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oocytes / cytology
  • Oocytes / growth & development
  • Organ Culture Techniques
  • Ovarian Follicle / cytology
  • Ovarian Follicle / embryology*
  • Ovulation / genetics
  • Primary Ovarian Insufficiency / genetics
  • Protein Folding
  • Transforming Growth Factor beta / metabolism


  • Bmp15 protein, mouse
  • Bone Morphogenetic Protein 15
  • Calreticulin
  • Gdf9 protein, mouse
  • Growth Differentiation Factor 9
  • Transforming Growth Factor beta
  • Calnexin