What have we learned about gonadotropin function from gonadotropin subunit and receptor knockout mice?

Abstract

A number of biochemical and physiological studies elucidated the roles of pituitary and placental glycoprotein hormones. Advances in the past two decades in manipulating the mouse genome by random or site-specific mutagenesis have heralded a new dimension to our understanding of the biology of gonadotropins. It is now possible to model many human reproductive disorders involving gonadotropins/gonadotropin-signaling in the mouse. Mutant mice selectively lacking either FSH or LH or their cognate receptors have been generated. The gonadotropin ligand and the corresponding receptor knockout mice mostly phenocopy each other. Analyses with these genetic models confirmed earlier physiological studies; in addition they also revealed novel roles for gonadotropins previously unrecognized. While FSH action seems dispensable for male but not female fertility, absence of LH causes infertility in both the sexes. While Sertoli cell number and germ cell carrying capacity of the Sertoli cells in compromised in FSH mutants, both somatic and germ cell lineages are affected in the LH mutants resulting in complete male infertility. FSH mutant females demonstrate a pre-antral stage block in folliculogenesis and FSH alone is not sufficient to promote full folliculogenesis in the absence of LH. Pre-ovulatory stage follicles do not form and most of the follicles undergo apoptosis in the absence of LH. Many extra-gonadal phenotypes have been described for the receptor knockout mice and whether these bear any resemblances to those in patients with similar inactivating mutations in the receptors for FSH and LH remains an open question. Thus the in vivo models will continue to have a significant impact in understanding gonadotropin physiology and pathophysiology and serve as novel genetic tools to study signaling mechanisms in the gonads.

Oligozoospermia with normal fertility in male mice lacking the androgen receptor in testis peritubular myoid cells

“…This finding is not surprising as it was reported that an impact on fertility should have an estimated sperm count reduction to 10% or less (22). Furthermore, previous reports have demonstrated several animal models with reduced sperm count but normal fertility (22)(23)(24)(25)(26). ADP-ribosylation factor-like 4 (Arl4) is a GTP-binding protein that shuttles between the nucleus and intracellular organelles depending on GTP͞GDP-binding status.…”

“…Schürmann et al (23) have demonstrated that Arl4 null mice have 30% reduction in testis weight and a 60% reduction in sperm count, but do not have a reduction in litter size or frequency. In addition, FSH␤ has been reported to play a role in spermatogenesis and mice lacking FSH␤ are also fertile despite having a reduced testis size and epididymal sperm count (25,26). Furthermore, centromere protein B is a DNA-binding protein required for meiosis, and its deletion caused a reduction in testis weight by 30% and a 40% reduction in sperm count without a reduction in fertility (24).…”

Loss of polyadenylation protein τCstF-64 causes spermatogenic defects and male infertility

“…Because there were no anatomical differences in reproductive organs among male Cstf2t ϩ/ϩ , Cstf2t ϩ/Ϫ , and Cstf2t Ϫ/Ϫ mice (SI Fig. 5B and Table 2), this suggested that the infertility was not due to major developmental or hormonal blockages in spermatogenesis (14).…”

Gonadotrope-specific Deletion of Dicer Results in Severely Suppressed Gonadotropins and Fertility Defects

“…Fshb/Fshr null females mostly phenocopy each other and demonstrate a pre-antral stage block in ovarian folliculogenesis (85,86). Lhb/Lhr null females also phenocopy each other and display a pre-ovulatory stage block in ovarian folliculogenesis (69,87,88).…”

“…Dicer cKO Female Mice Display Fertility Defects-Loss of gonadotropins and their cognate receptors results in impairment of ovarian folliculogenesis at distinct phases of ovarian development (85,86). Fshb/Fshr null females mostly phenocopy each other and demonstrate a pre-antral stage block in ovarian folliculogenesis (85,86).…”