Minimal fertility defects in mice deficient in oocyte-expressed Smad4

Biol Reprod. 2012 Jan 30;86(1):1-6. doi: 10.1095/biolreprod.111.094375. Print 2012 Jan.


Bidirectional signaling between oocytes and granulosa cells is required for normal folliculogenesis. Oocyte-secreted members of the transforming growth factor beta (TGFB) family, growth differentiation factor 9 (GDF9), and bone morphogenetic protein 15 (BMP15) are well-known mediators of granulosa cell function. Deletion in granulosa cells of Smad4, the common SMAD mediating all canonical TGFB-related protein signals, results in infertility. Reciprocal signaling by granulosa cell-expressed TGFB family ligands, such as activin, to the oocyte during follicle development has been proposed but not tested in vivo using conditional knockout mice. Therefore, we generated two oocyte-specific conditional knockout models for the common SMAD, Smad4, using cre recombinase expression from either the zona pellucida 3 (Zp3) or Gdf9 promoter. Cre expression from the Gdf9 promoter occurs at a slightly earlier time point in follicle development than from Zp3. Deletion of Smad4 using Zp3cre had no effect on fertility, while deletion of Smad4 with Gdf9icre resulted in a slight, but significant, reduction in litter size. These mouse models suggest a novel, although minor, role for Smad4 in the oocyte restricted to the primordial follicle stage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Egg Proteins / genetics
  • Egg Proteins / metabolism
  • Female
  • Fertility / genetics*
  • Gene Expression Regulation / physiology
  • Granulosa Cells / metabolism
  • Growth Differentiation Factor 9 / genetics
  • Growth Differentiation Factor 9 / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Knockout
  • Oocytes / metabolism*
  • Ovary / anatomy & histology
  • Ovary / physiology
  • Ovulation / physiology
  • Promoter Regions, Genetic
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism*
  • Zona Pellucida Glycoproteins


  • Egg Proteins
  • Gdf9 protein, mouse
  • Growth Differentiation Factor 9
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • Smad4 Protein
  • Smad4 protein, mouse
  • Zona Pellucida Glycoproteins
  • Zp3 protein, mouse