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Submitted on September 17, 2003
Accepted on January 15, 2004
Reproductive Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
* To whom correspondence should be addressed. E-mail: Schneyer.alan{at}mgh.harvard.edu.
Activin has numerous biological activities including regulation of follicular development, spermatogenesis and steroidogenesis within the gonads. Activities of activin are regulated by follistatin (FST), an activin binding protein, and perhaps follistatin-like 3 (FSTL3; aka FLRG, FSRP). FSTL3 is a recently described member of follistatin family having an overall structure and activity profile similar to that of FST, including binding and neutralization of activin. FSTL3 is most highly expressed in the placenta and testis whereas FST is highest in the ovary and kidney, suggesting that FSTL3 has biologic actions that do not entirely overlap those of FST. To investigate the role of local FSTL3 as a potential regulator of activin action in gonad development and function, we examined FSTL3 expression in the mouse testis. FSTL3 protein was localized to Leydig cells, spermatagonia, and mature spermatids in normal male mice. We then created transgenic mice using an hFSTL3 cDNA driven by the mouse 
-inhibin promoter. Three of five transgenic founders were fertile and were bred to establish lines. In the highest expressing line 3, transgene expression was largely restricted to gonads, with pituitary, adrenal, brain and uterine expression being substantially lower. Gonad weights, sperm counts and fertility were significantly reduced in transgenic males and reduced litter size was evident in line 3 females. Within the testis, highest transgene expression was observed in Sertoli cells, and although most tubules showed evidence of normal spermatogenic development, degenerating tubules devoid of germ cells and Leydig cell hyperplasia were also evident in every line 3 animal examined. Ovaries from line 3 females contained fewer antral follicles and more apparent follicular atresia. While circulating hFSTL3 levels were undetectable, FSH and LH levels in adult transgenic mice were not significantly different from wild type animals. However, testosterone levels were significantly increased at day 21 and significantly reduced at day 60 compared with wild type males. These results suggest that FSTL3 is likely to be a local regulator of activin action in gonadal development and gametogenesis, and further, that activin appears to have important actions in gonadal development and function that are critical for normal reproduction.
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