Synexpression group analyses identify new functions of FSTL3, a TGFβ ligand inhibitor.

Follistatin-like 3 (FSTL3) is a secreted glycoprotein that forms inactive complexes with and acts as an endogenous inhibitor of TGFβ ligands such as activin, myostatin and GDF11. FSTL3 gene deleted mice (FSTL3 KO) are viable, fertile and show a constellation of metabolic abnormalities, including those involving glucose and lipid homoeostasis, suggesting a role for FSTL3 and TGFβ ligand signaling in these systems. To identify additional roles of FSTL3 and the ligands it inhibits we have used a synexpression analysis strategy. By mining microarray RNA expression data we have identified a group of 9 genes, the expression of which closely follow that of FSTL3 in both mouse and human tissues. After classifying the tissues studied according to physiological systems we found that within each system the expression of a majority, but not all, of the genes are strongly correlated with FSTL3 expression. Further, the best correlation of expression was seen in the cardiovascular system. Importantly, the promoter regions of a number of these synexpression genes have putative SMAD binding elements and in cultured embryonic fibroblasts the expression of a subset of these genes are induced in the absence of FSTL3 or in WT cells upon activin treatment. Taken together, we have identified a group of activin responsive genes the expression of which is closely related to and regulated by FSTL3. These findings link FSTL3 and TGFβ ligand signaling and a novel subset of the synexpression group of genes to organ/tissue-specific regulatory pathways.