Conditional deletion of FOXL2 and SMAD4 in gonadotropes of adult mice causes isolated FSH deficiency


  • Y. Li
  • G. Schang
  • Y. Wang
  • X. Zhou
  • A. Levasseur
  • A. Boyer
  • C.X. Deng
  • M. Treier
  • U. Boehm
  • D. Boerboom
  • D.J. Bernard


  • Endocrinology


  • Endocrinology 159 (7): 2641-2655


  • The glycoprotein follicle-stimulating hormone (FSH), a product of pituitary gonadotrope cells, regulates ovarian follicle development in females and spermatogenesis in males. FSH is a heterodimer of the common α gonadotropin subunit and the hormone-specific FSHβ subunit (a product of the Fshb gene). Using a conditional knockout approach (Cre-lox), we previously demonstrated that Fshb expression in mice depends on the transcription factors FOXL2 and SMAD4. Deletion of Foxl2 or Smad4 alone led to FSH deficiency, female subfertility, and oligozoospermia in males. Simultaneous deletion of the two genes yielded a greater suppression of FSH and female sterility. The Cre-driver used previously was first active during embryonic development. Therefore, it is unclear whether FOXL2 and SMAD4 play important roles in the development or adult function of gonadotropes, or both. To address this question, we developed a novel, tamoxifen-inducible Cre-driver line, which enabled Foxl2 and Smad4 gene deletions in gonadotropes of adult mice. Following tamoxifen treatment, females with previously demonstrated fertility exhibited profound reductions in FSH levels, arrested ovarian follicle development, and sterility. FSH levels were comparably reduced in males one or two months post-treatment; however, spermatogenesis was unaffected. These data indicate that: 1) FOXL2 and SMAD4 are required to maintain FSH synthesis in gonadotrope cells of adult mice, 2) FSH is essential for female reproduction, but appears to be dispensable for the maintenance of spermatogenesis in adult male mice, and 3) the inducible Cre-driver line developed here provides a powerful new tool to interrogate gene function in gonadotrope cells of adult mice.