R-spondins and LGRs

R-spondin (Rspo) proteins are  secreted proteins defined by two N-terminal furin domains and a thrombospondin domain (Kazanskaya et al, 2004; Kim et al, 2005; reviewed in  MacDonald and He (2012),  Niehrs (2012)). They enhance Wnt/b-catenin signals in various contexts. Unlike Wnts themselves, which work locally, Rspo proteins have systemic effects. Rspo mutations have been found in several hereditary syndromes in humans (Table below). RSPO1 is disrupted in a recessive syndrome characterized by XX sex reversal, a skin abnormality called palmoplantar hyperkeratosis, and predisposition to squamous cell carcinomas. Mutations in the RSPO4 gene are linked to congenital anonychia, severe hypo- plasia of finger- and toenails. 

Rspo proteins use members of  the Lgr family as receptors  (Glinka et al, 2011Carmon et al, 2011De Lau et al, 2011). (see Figure), in particular in stem cells and thereby have input into the canonical Wnt pathway. The receptors are related to G-protein-coupled receptors for thyroid-stimulating hormone,  follicle-stimulating hormone and luteinizing hormone. These receptors contain a large N-terminal extracellular leucine-rich repeat domain that binds the glycoprotein hormones. Similarly, the Lgr proteins bind R-spondins through their N-terminal ectodomain, but current evidence indicates that they do not utilize G proteins (Carmon et al, 2011De Lau et al, 2011). 

Lgr4 as well as Lgr5 mutant mice are neonatal lethal.  Lgr5 is a Wnt target gene in colon cancer and that it marks adult stem cells in a number of actively self-renewing organs, including the intestinal tract and the hair follicle (reviewed in Clevers and Nusse, 2012) The finding that the Lgr proteins act as receptors for Rspo molecules reinforces the connections between Wnt signaling and activation of adult stem cells. 

 

Human gene

 Disease

Mouse gene

Mouse phenotype 

RSPO1Palmoplantar hyperkeratosisRspo1abnormal ovarian development 
RSPO2 Rspo2 
RSPO3 Rspo3 embryonic lethality 
RSPO4

congenital anonychia 

Rspo4

Human gene

 Disease

Mouse gene

Mouse phenotype 

LGR4Bone density effectsLgr4embryonic and perinatal death
LGR5 Lgr5neonatal lethality 
LGR6 Lgr6no apparent phenotype