The Follistatin-288 Isoform Alone Is Sufficient for Survival But Not for Normal Fertility in Mice

Abstract

Follistatin (FST) is a natural antagonist of activin and related TGFbeta superfamily ligands that exists as three protein isoforms differing in length at the C terminus. The longest FST315 isoform is found in the circulation, whereas the shortest FST288 isoform is typically found in or on cells and tissues, and the intermediate FST303 isoform is found in gonads. We recently demonstrated that the FST isoforms have distinct biological actions in vitro that, taken together with the differential distribution, suggests they may also have different roles in vivo. To explore the specific role of individual FST isoforms, we created a single-isoform FST288-only mouse. In contrast to the neonatal death of FST global knockout mice, FST288-only mice survive to adulthood. Although they appear normal, FST288-only mice have fertility defects including reduced litter size and frequency. Follicles were counted in ovaries from 8.5- to 400-d-old females. Significantly fewer morphologically healthy antral follicles were found in 100- to 250-d FST288-only ovaries, but there were significantly more secondary, primary, and primordial follicles detected at d 8.5 in FST288-only ovaries. However, depletion of this primordial follicle pool is more rapid in FST288-only females resulting in a deficit by 250 d of age and early cessation of reproduction. Superovulated FST288-only females have fewer ovulated eggs and embryos. These results indicate that the FST isoforms have different activities in vivo, that the FST288-only isoform is sufficient for development, and that loss of FST303 and FST315 isoforms results in fertility defects that resemble activin hyperactivity and premature ovarian failure.

Follistatin is essential for normal postnatal development and function of mouse oviduct and uterus

“…We were unable to fully address the isoform-specific roles of FST288 and FST315 (and FST303) proteins due in part to the lack of commercially available isoform-specific FST antibodies and, secondly, due to our inability to study tghFST288 mice beyond PND0. Additional studies using the mutant mouse line expressing mouse FST288 only would be valuable (Kimura et al 2010). Further, although tghFST315 mice survive to adulthood with complete reversal of the abnormal lung phenotype in the FSTKO (Lin et al 2008), the serum levels of FST are significantly lower than in WT mice.…”

“…Various transgenic mouse models have been developed as tools to study the developmental and functional roles of FST (Matzuk et al 1995;Guo et al 1998;Wankell et al 2001;Jorgez et al 2004;Lin et al 2008;Kimura et al 2010). However, complete deletion of Fst resulted in death shortly after birth (Matzuk et al 1995) due to respiratory failure associated with thickened alveolar walls (Lin et al 2008), therefore preventing examination of the role of FST in adult mice.…”

Dynamic expression of bone morphogenetic protein 4 in reproductive organs of female mice

“…Various BMP signaling antagonists and agonists such as dragon, gremlin, and follistatin are expressed in the mammalian ovary and are likely to play an an important role in the regulation of ovarian function (Pangas et al 2004, Xia et al 2004, Kimura et al 2010, suggesting that modulation of BMP signaling by various factors is required for normal ovarian function. The significance of BMP signaling in the ovary is further highlighted by the increased ovulation rates in Booroola sheep with a point mutation in BMPR1B gene (Mulsant et al 2001, Souza et al 2001, Wilson et al 2001.…”

Canonical TGF-β Signaling Is Required for the Balance of Excitatory/Inhibitory Transmission within the Hippocampus and Prepulse Inhibition of Acoustic Startle

“…9A), an extracellular antagonist that binds both activin and BMP ligands. Both exon 3 and exon 6 of fst are increased in Smad4 KO hippocampi, suggesting that all the RNA splicing isoforms of follistatin (Sugino et al, 1993;Kimura et al, 2010) are upregulated in Smad4 KO hippocampi. We did not detect significant changes in other extracellular TGF-␤ inhibitors such as fstl1, chrd, and nog in either the TGF-␤ pathway array or QPCR assays.…”