R-spondin 1 explained

R-spondin-1 is a secreted protein that in humans is encoded by the RSPO1 gene, found on chromosome 1.^[1] In humans, it interacts with WNT4 in the process of female sex development. Loss of function can cause female to male sex reversal.^[2] Furthermore, it promotes canonical WNT/β catenin signaling.^[3]

Structure

The protein has two cysteine-rich, furin-like domains and one thrombospondin type 1 domain.

Function

Sex Development

Early Gonads

RSPO1 is required for the early development of gonads, regardless of sex. It has been found in mice only eleven days after fertilization. To induce cell proliferation, it acts synergistically with WNT4. They help stabilize β-catenin, which activates downstream targets. If both are deficient in XY mice, there is less expression of SRY and a reduction in the amount of SOX9. Moreover, defects in vascularization are found. These occurrences result in testicular hypoplasia. Male to female sex reversal, however, does not occur because Leydig cells remain normal. They are maintained by steroidogenic cells, now unrepressed.

Ovaries

RSPO1 is necessary in female sex development. It augments the WNT/β catenin pathway to oppose male sex development. In critical gonadal stages, between six and nine weeks after fertilization, the ovaries upregulate it while the testes downregulate it.^[4]

Mucositis

Oral mucosa has been identified as a target tissue for RSPO1. When administered to normal mice, it causes nuclear translocation of β-catenin to this region. Modulation of the WNT/β catenin pathway occurs through the relief of Dkk1 inhibition. This occurrence results in increased basal cellularity, thickened mucosa, and elevated epithelial cell proliferation in the tongue. RSPO1 can therefore potentially aid in the treatment of mucositis, which is characterized by inflammation of the oral cavity. This unfortunate condition often accompanies chemotherapy and radiation in cancer patients with head and neck tumors. RSPO1 has also been shown to promote gastrointestinal epithelial cell proliferation in mice.

Further reading

• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Ota T, Suzuki Y, Nishikawa T, etal . Complete sequencing and characterization of 21,243 full-length human cDNAs . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . free .
• Kamata T, Katsube K, Michikawa M, etal . R-spondin, a novel gene with thrombospondin type 1 domain, was expressed in the dorsal neural tube and affected in Wnts mutants . Biochim. Biophys. Acta . 1676 . 1 . 51–62 . 2004 . 14732490 . 10.1016/j.bbaexp.2003.10.009.
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC) . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Kim KA, Kakitani M, Zhao J, etal . Mitogenic influence of human R-spondin1 on the intestinal epithelium . Science . 309 . 5738 . 1256–9 . 2005 . 16109882 . 10.1126/science.1112521 . 2005Sci...309.1256K . 45221785 .
• Abraham C, Cho JH . Inducing intestinal growth . N. Engl. J. Med. . 353 . 21 . 2297–9 . 2005 . 16306530 . 10.1056/NEJMcibr053367 .
• Kimura K, Wakamatsu A, Suzuki Y, etal . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes . Genome Res. . 16 . 1 . 55–65 . 2006 . 16344560 . 10.1101/gr.4039406 . 1356129 .
• Gregory SG, Barlow KF, McLay KE, etal . The DNA sequence and biological annotation of human chromosome 1 . Nature . 441 . 7091 . 315–21 . 2006 . 16710414 . 10.1038/nature04727 . 2006Natur.441..315G . free .
• Parma P, Radi O, Vidal V, etal . R-spondin1 is essential in sex determination, skin differentiation and malignancy . Nat. Genet. . 38 . 11 . 1304–9 . 2007 . 17041600 . 10.1038/ng1907 . 9687808 .
• Binnerts ME, Kim KA, Bright JM, etal . R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6 . Proc. Natl. Acad. Sci. U.S.A. . 104 . 37 . 14700–5 . 2007 . 17804805 . 10.1073/pnas.0702305104 . 1965484 . 2007PNAS..10414700B . free .

Notes and References

1. Web site: Entrez Gene: RSPO1 R-spondin homolog (Xenopus laevis).
2. Chassot . A. -A. . Bradford . S. T. . Auguste . A. . Gregoire . E. P. . Pailhoux . E. . De Rooij . D. G. . Schedl . A. . Chaboissier . M. -C. . 10.1242/dev.078972 . WNT4 and RSPO1 together are required for cell proliferation in the early mouse gonad . Development . 139 . 23 . 4461–4472 . 2012 . 23095882 . free .
3. Zhao . J. . Kim . K. -A. . De Vera . J. . Palencia . S. . Wagle . M. . Abo . A. . 10.1073/pnas.0805159106 . R-Spondin1 protects mice from chemotherapy or radiation-induced oral mucositis through the canonical Wnt/ -catenin pathway . Proceedings of the National Academy of Sciences . 106 . 7 . 2331–2336 . 2009 . 19179402 . 2650156 . free .
4. Tomaselli . S. . Megiorni . F. . Lin . L. . Mazzilli . M. C. . Gerrelli . D. . Majore . S. . Grammatico . P. . Achermann . J. C. . Lee . Sean . 10.1371/journal.pone.0016366 . Human RSPO1/R-spondin1 is Expressed during Early Ovary Development and Augments β-Catenin Signaling . PLOS ONE . 6 . 1 . e16366 . 2011 . 21297984 . 3030573 . 2011PLoSO...616366T . free .