Uterine abnormalities in mice lacking the follistatin gene and expressing a human follistatin-315 transgene (#174)
Follistatin (FST), an inhibitor of Activin A activity, has fundamental roles in female reproduction. FST has two splice variants: FST288 is associated with cell surfaces; FST315 is the circulating form. Female mice with both a targeted deletion of the mouse FST gene and expressing a human FST315 transgene (tghFST315) have severe reproductive abnormalities (reduced ovarian follicular population, no corpora lutea, and increased ovarian and uterine inflammation)1. This study characterised the morphology of tghFST315 oviducts and uteri. We postulated that tract defects reflected abnormalities of ovarian function. The reproductive tracts (oviduct, uterus) of WT and tghFST315 mice were examined in neonatal (day 0), pre-pubertal (4w) and adult mice (8w) using histology and immunohistochemistry (αSMA, CD31, CD45). To remove the influence of abnormal ovaries, adult WT and tghFST315 mice were ovariectomised and treated with vehicle, exogenous oestradiol-17B (100ng s.c. injection, dissection after 24h) or progesterone (1mg x 3 daily s.c. injections, dissection 24h after last injection) (n=6 per group). The oviduct and uterus of tghFST315 mice at birth were not different to WTs, but abnormalities were observed as early as 4w of age. In contrast to WT mice, the oviducts of tghFST315 mice failed to coil and the myometrial muscle layers were disorganised. Uteri/oviducts contained abundant CD45 positive leucocytes. Preliminary analysis suggests that endometrial cell proliferation in tghFST315 mice in response to exogenous E or P is consistent with that of WT mice, but the abundant CD45 leucocyte infiltration was not resolved by ovariectomy. We conclude that absent oviductal coiling and disorganisation of the myometrium represent a developmental defect of the Mullerian duct resulting from FST288 absence. The mechanism responsible for the oviductal/uterine inflammation, which develops after sexual maturity (suggesting oestradiol involvement) but is not resolved by ovariectomy (absence of ovarian steroids), has yet to be determined.
- Lin, S.Y., et al., Female infertility and disrupted angiogenesis are actions of specific follistatin isoforms. Mol Endocrinol, 2008. 22(2): p. 415-29.