Follistatin-like 1 in development and human diseases

Abstract

Follistatin-like 1 (FSTL1) is a secreted glycoprotein displaying expression changes during development and disease, among which cardiovascular disease, cancer, and arthritis. The cardioprotective role of FSTL1 has been intensively studied over the last years, though its mechanism of action remains elusive. FSTL1 is involved in multiple signaling pathways and biological processes, including vascularization and regulation of the immune response, a feature that complicates its study. Binding to the DIP2A, TLR4 and BMP receptors have been shown, but other molecular partners probably exist. During cancer progression and rheumatoid arthritis, controversial data have been reported with respect to the proliferative, apoptotic, migratory, and inflammatory effects of FSTL1. This controversy might reside in the extensive post-transcriptional regulation of FSTL1. The FSTL1 primary transcript also encodes for a microRNA (miR-198) in primates and multiple microRNA-binding sites are present in the 3′UTR. The switch between expression of the FSTL1 protein and miR-198 is an important regulator of tumour metastasis and wound healing. The glycosylation state of FSTL1 is a determinant of biological activity, in cardiomyocytes the glycosylated form promoting proliferation and the non-glycosylated working anti-apoptotic. Moreover, the glycosylation state shows differences between species and tissues which might underlie the differences observed in in vitro studies. Finally, regulation at the level of protein secretion has been described.Electronic supplementary materialThe online version of this article (10.1007/s00018-018-2805-0) contains supplementary material, which is available to authorized users.

Structural and functional study of FK domain of Fstl1

“…Follistatin‐like 1 (Fstl1) is a secreted, 308 amino‐acid matricellular protein belonging to a group of matrix‐related factors that mediate cell–matrix interactions but do not serve primarily structural roles . Expression of Fstl1 is generally associated with tissue undergoing remodeling, either during normal developmental process or as a response to injury . During embryogenesis, the expression of Fstl1 is temporarily and spatially regulated and loss‐of‐function experiments have unveiled an important role for Fstl1 in dorsoventral axis establishment, lung, skeletal, and ureter developments .…”

“…1,2 Expression of Fstl1 is generally associated with tissue undergoing remodeling, either during normal developmental process or as a response to injury. 3,4 During embryogenesis, the expression of Fstl1 is temporarily and spatially regulated and loss-of-function experiments have unveiled an important role for Fstl1 in dorsoventral axis establishment, lung, 5 skeletal, 6 and ureter developments. 7 Fstl1 has been implicated in several human diseases.…”

Loss of FSTL1-expressing adipocyte progenitors drives the age-related involution of brown adipose tissue

“…Next, we then set out to explore whether the FSTL1 genes was functionally important for FSTL1 high brown adipocyte progenitors. The encoded glycoprotein follistatin like 1 belongs to the secreted protein acid and rich in cysteine (SPARC) family that has a role in lung development, muscle function, and cardioprotection (Mattiotti et al, 2018a). However, whether it controls iBAT development and involution has not been explored.…”

“…FSLT1 displays comparable expression patterns to DLK1, and thus may have an analogous function in adipogenesis. FSTL1 is involved in multiple signaling pathways, and many of its biological functions have been attributed to its inhibition to BMP signaling by competitively binding to BMP4 (Geng et al, 2011;Mattiotti et al, 2018b). However, BMP signaling has been widely recognized to promote the commitment of mesenchymal stem cells into the adipogenic lineage (Tang and Lane, 2012;Lee, 2018).…”

Zebrafishfollistatin-like 1bregulates cardiac contraction during early development

“…Follistatin-like protein 1 (FSTL1) is an extracellular glycoprotein belonging to the secreted protein acid and rich in cysteine (SPARC) family containing both extracellular calcium-binding and follistatin-like domains (1,2). FSTL1 is involved in multiple signaling pathways and biological processes during development and disease, including cardiovascular disease, cancer, and arthritis (3,4). Functional disruption of Fstl1 in mice has demonstrated its important roles in early development and organogenesis, such as lung (5,6), skeletal tissues (6), and ureter (7).…”