R-spondin signaling as a pivotal regulator of tissue development and homeostasis

R-spondins (Rspos) are cysteine-rich secreted glycoproteins which control a variety of cellular functions and are essential for embryonic development and tissue homeostasis. R-spondins (Rspo1 to 4) have high structural similarity and share 60% sequence homology. It has been shown that their cysteine-rich furin-like (FU) domain and the thrombospondin (TSP) type I repeat domain are essential for initiating downstream signaling cascades and therefore for their biological functions. Although numerous studies have unveiled their pivotal role as critical developmental regulators, the most important finding is that Rspos synergize Wnt signaling. Recent studies have identified novel receptors for Rspos, the Lgr receptors, closely related orphans of the leucin-rich repeat containing G protein-coupled receptors, and proposed that Rspos potentiate canonical Wnt signaling via these receptors. Given that Wnt signaling is one of the most important developmental signaling pathways that controls cell fate decisions and tissue development, growth and homeostasis, Rspos may function as key players for these processes as well as potential therapeutic targets. Here, I recapitulate the Wnt signaling and then outline the biological role of Rspos in tissue development and homeostasis and explore the possibility that Rspos may be used as therapeutic targets.