Endocrine Abstracts

Follistatin like 3 (FSTL-3) is an endogenous inhibitor that binds and inhibits TGFβ family ligands such as activin, myostatin and GDF11. Activin plays crucial roles in development, cellular proliferation and apoptosis while myostatin is a known blocker of muscle growth. To identify physiological roles of FSTL3, FSTL3 gene deletion mice (FSTL3 KO) were generated which displayed altered glucose and lipid metabolism phenotypes. To address the role of FSTL3 in cellular biology, an aspect which has not yet been studied, we generated mouse embryonic fibroblasts from FSTL3 KO and FSTL3 conditional/ “floxed” (wildtype, WT) mouse embryos. Using these cells we investigated whether cellular proliferation and signalling are altered as a result of FSTL3 deletion. We found that FSTL3 KO MEFs show significantly increased proliferation in serum fed conditions compared to control WT cells. To elucidate the cellular signalling pathways that are altered by FSTL3 gene deletion which might affect cellular proliferation, we investigated Smad and ERK activation profiles in the presence or absence of activin using the MEF cells. In WT MEFs, we found Smad2 phosphorylation to be significantly enhanced in the presence of exogenous activin, an effect which is reversed following treatment with FSTL3. In the absence of endogenous FSTL3 (KO MEFs), activin-induced Smad2 phosphorylation is also suppressed after treatment with inhibitor but the levels of phospho-Smad2 remain higher compared to WT MEFs, possibly a reflection of reduced inhibition of activin in the absence of FSTL3. In addition, levels of phosphorylated p42/44 ERK proteins, which play important roles in the regulation of cell growth, were also higher in KO MEFs compared to WT. Taken together, our data demonstrate a novel role for FSTL3 in the regulation of cellular proliferation and suggest that Smad and ERK signalling pathways might contribute to this function.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.