Skip to main content
Log in

Expression pattern of the orphan receptor LGR4/GPR48 gene in the mouse

  • Original paper
  • Published:
Histochemistry and Cell Biology Aims and scope Submit manuscript

Abstract

Leucine-rich G-protein-coupled Receptors (LGR) constitute a subfamily of receptors related to glycoprotein hormone receptors. Amongst them, LGR4, LGR5 and LGR6 form a cluster for which natural agonists are still unknown. By an extensive gene trapping approach, Leighton et al. (2001) obtained a mouse line in which the LGR4 gene is disrupted by a trap vector carrying two biological markers, beta-geo (a fusion between bacterial beta-galactosidase and neomycin phosphotransferase) and a placental alkaline phosphatase (PLAP). Due to perinatal lethality, characterization of adult mice homozygous for this insertion has been impaired. In the present study we have investigated LacZ and PLAP activity patterns in heterozygous mice as a marker for LGR4 natural expression at both macroscopic and histological levels. We present a detailed atlas of LGR4 expression, which displays very wide expression with particularly strong activity in cartilages, kidneys, reproductive tracts and nervous system cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

References

  • Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, Louden CS, Foley JJ, Sauermelch CF, Coatney RW, Ao Z, Disa J, Holmes SD, Stadel JM, Martin JD, Liu WS, Glover GI, Wilson S, McNulty DE, Ellis CE, Elshourbagy NA, Shabon U, Trill JJ, Hay DW, Douglas SA (1999) Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 401(6750):282–286. Erratum (1999) in : Nature 402(6764):898

    Google Scholar 

  • Ascoli M, Fanelli F, Segaloff DL (2002) The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev 23(2):141–174

    Article  PubMed  CAS  Google Scholar 

  • Avram CE, Cooper TG (2004) Development of the caput epididymidis studied by expressed proteins (a glutamate transporter, a lipocalin and beta-galactosidase) in the c-ros knockout and wild-type mice with prepubertally ligated efferent ducts. Cell Tissue Res 317(1):23–34

    PubMed  CAS  Google Scholar 

  • Blanpain C, Lowry WE, Geoghegan A, Polak L, Fuchs E (2004) Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118(5):635–648

    Article  PubMed  CAS  Google Scholar 

  • Braun T, Schofield PR, Sprengel R (1991) Amino-terminal leucine-rich repeats in gonadotropin receptors determine hormone selectivity. EMBO J 10(7):1885–1890

    PubMed  CAS  Google Scholar 

  • Civelli O, Nothacker HP, Saito Y, Wang Z, Lin SH, Reinscheid RK (2001) Novel neurotransmitters as natural ligands of orphan G-protein-coupled receptors. Trends Neurosci 24(4):230–237

    Article  PubMed  CAS  Google Scholar 

  • Dias JA, Van Roey P (2001) Structural biology of human follitropin and its receptor. Arch Med Res 32(6):510–519

    Article  PubMed  CAS  Google Scholar 

  • Hauser F, Nothacker HP, Grimmelikhuijzen CJ (1997) Molecular cloning, genomic organization, and developmental regulation of a novel receptor from Drosophila melanogaster structurally related to members of the thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone/choriogonadotropin receptor family from mammals. J Biol Chem 272(2):1002–1010

    Article  PubMed  CAS  Google Scholar 

  • Hermey G, Methner A, Schaller HC, Hermans-Borgmeyer I (1999) Identification of a novel seven-transmembrane receptor with homology to glycoprotein receptors and its expression in the adult and developing mouse. Biochem Biophys Res Commun 254(1):273–279

    Article  PubMed  CAS  Google Scholar 

  • Herpin A, Badariotti F, Rodet F, Favrel P (2004) Molecular characterization of a new leucine-rich repeat-containing G protein-coupled receptor from a bivalve mollusc: evolutionary implications. Biochim Biophys Acta. 1680(3):137–144

    PubMed  CAS  Google Scholar 

  • Hsu SY (2003) New insights into the evolution of the relaxin-LGR signaling system. Trends Endocrinol Metab 14(7):303–309

    Article  PubMed  CAS  Google Scholar 

  • Hsu SY, Liang SG, Hsueh AJ (1998) Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Mol Endocrinol 12:1830–1845

    Article  PubMed  CAS  Google Scholar 

  • Hsu SY, Kudo M, Chen T, Nakabayashi K, Bhalla A, van der Spek PJ, van Duin M, Hsueh AJ (2000) The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7. Mol Endocrinol 14(8):1257–1271

    Article  PubMed  CAS  Google Scholar 

  • Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, Hsueh AJ (2002) Activation of orphan receptors by the hormone relaxin. Science 295(5555):671–674

    Article  PubMed  CAS  Google Scholar 

  • Huizinga EG, Tsuji S, Romijn RA, Schiphorst ME, de Groot PG, Sixma JJ, Gros P (2002) Structures of glycoprotein Ibalpha and its complex with von Willebrand factor A1 domain. Science 297(5584):1176–1179

    Article  PubMed  CAS  Google Scholar 

  • Kajava AV (1998) Structural diversity of leucine-rich repeat proteins. J Mol Biol 277:519–527

    Article  PubMed  CAS  Google Scholar 

  • Kobe B, Deisenhofer J (1995) Proteins with leucine-rich repeats. Curr Opin Struct Biol 5:409–416

    Article  PubMed  CAS  Google Scholar 

  • Kudo M, Chen T, Nakabayashi K, Hsu SY, Hsueh AJ (2000) The nematode leucine-rich repeat-containing, G protein-coupled receptor (LGR) protein homologous to vertebrate gonadotropin and thyrotropin receptors is constitutively active in mammalian cells. Mol Endocrinol 14(2):272–284

    Article  PubMed  CAS  Google Scholar 

  • Kumagai J, Hsu SY, Matsumi H, Roh JS, Fu P, Wade JD, Bathgate RA, Hsueh AJ (2002) INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent. J Biol Chem 277(35):31283–31286

    Article  PubMed  CAS  Google Scholar 

  • Lako M, Hole N (2000) Searching the unknown with gene trapping. Expert Rev Mol Med 2000:1–11

    Google Scholar 

  • Leighton PA, Mitchell KJ, Goodrich LV, Lu X, Pinson K, Scherz P, Skarnes WC, Tessier-Lavigne M (2001) Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature 410:174–179

    Article  PubMed  CAS  Google Scholar 

  • Luo CW, Dewey EM, Sudo S, Ewer J, Hsu SY, Honegger HW, Hsueh AJ (2005) Bursicon, the insect cuticle-hardening hormone, is a heterodimeric cystine knot protein that activates G protein-coupled receptor LGR2. Proc Natl Acad Sci USA 102(8):2820–2825

    Article  PubMed  CAS  Google Scholar 

  • Ma W, Rogers K, Zbar B, Schmidt L (2002) Effects of different fixatives on beta-galactosidase activity. J Histochem Cytochem 50(10):1421–1424

    PubMed  CAS  Google Scholar 

  • Mazerbourg S, Bouley DM, Sudo S, Klein C, Zhang JV, Kawamura K, Goodrich LV, Rayburn H, Tessier-Lavigne M, Hsueh AJ (2004) LGR4 receptor null mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality. Mol Endocrinol 18(9):2241–2254

    Article  PubMed  CAS  Google Scholar 

  • Mendive FM, Van Loy T, Claeysen S, Poels J, Williamson M, Hauser F, Grimmelikhuijzen CJP, Vassart G, Vanden Broeck J (2005) Drosophila molting neurohormone bursicon is a heterodimer and the natural agonist of the orphan receptor DLGR2. FEBS lett 579(10):2171–2176

    Article  PubMed  CAS  Google Scholar 

  • Mitchell KJ, Pinson KI, Kelly OG, Brennan J, Zupicich J, Scherz P, Leighton PA, Goodrich LV, Lu X, Avery BJ, Tate P, Dill K, Pangilinan E, Wakenight P, Tessier-Lavigne M, Skarnes W (2001) Functional analysis of secreted and transmembrane proteins critical to mouse development. Nat Genet 28(3):241–249

    Article  PubMed  CAS  Google Scholar 

  • Morita H, Mazerbourg S, Bouley DM, Luo CW, Kawamura K, Kuwabara Y, Baribault H, Tian H, Hsueh AJ (2004) Neonatal lethality of LGR5 null mice is associated with ankyloglossia and gastrointestinal distension.Mol Cell Biol 24(22):9736–9743

    Article  PubMed  CAS  Google Scholar 

  • Morris RJ, Liu Y, Marles L, Yang Z, Trempus C, Li S, Lin JS, Sawicki JA, Cotsarelis G (2004) Capturing and profiling adult hair follicle stem cells. Nat Biotechnol 22(4):411–417

    Article  PubMed  CAS  Google Scholar 

  • Nagayama Y, Wadsworth HL, Chazenbalk GD, Russo D, Seto P, Rapoport B (1991) Thyrotropin-luteinizing hormone/chorionic gonadotropin receptor extracellular domain chimeras as probes for thyrotropin receptor function. Proc Natl Acad Sci USA 88(3):902–905

    Article  PubMed  CAS  Google Scholar 

  • Nakabayashi K, Matsumi H, Bhalla A, Bae J, Mosselman S, Hsu SY, Hsueh AJ (2002) Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor. J Clin Invest 109(11):1445–1452

    Article  PubMed  CAS  Google Scholar 

  • Nishi S, Hsu SY, Zell K, Hsueh AJ (2000) Characterization of two fly LGR (leucine-rich repeat-containing, G protein-coupled receptor) proteins homologous to vertebrate glycoprotein hormone receptors: constitutive activation of wild-type fly LGR1 but not LGR2 in transfected mammalian cells. Endocrinology 141(11):4081–4090

    Article  PubMed  CAS  Google Scholar 

  • Nishi S, Nakabayashi K, Kobilka B, Hsueh AJ (2002) The ectodomain of the luteinizing hormone receptor interacts with exoloop 2 to constrain the transmembrane region: studies using chimeric human and fly receptors. J Biol Chem 277(6):3958–3964

    Article  PubMed  CAS  Google Scholar 

  • Nothacker HP, Grimmelikhuijzen CJ (1993) Molecular cloning of a novel, putative G protein-coupled receptor from sea anemones structurally related to members of the FSH, TSH, LH/CG receptor family from mammals. Biochem Biophys Res Commun 197(3):1062–1069. Erratum (1994) in : Biochem Biophys Res Commun 200(1):668

    Google Scholar 

  • Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92(4):573–585

    Article  PubMed  CAS  Google Scholar 

  • Skarnes WC, Moss JE, Hurtley SM, Beddington RS (1995) Capturing genes encoding membrane and secreted proteins important for mouse development. Proc Natl Acad Sci USA 92(14):6592–6596

    Article  PubMed  CAS  Google Scholar 

  • Smits G, Campillo M, Govaerts C, Janssens V, Richter C, Vassart G, Pardo L, Costagliola S (2003) Glycoprotein hormone receptors: determinants in leucine-rich repeats responsible for ligand specificity. EMBO J 22(11):2692–2703

    Article  PubMed  CAS  Google Scholar 

  • Stumpp MT, Forrer P, Binz HK, Pluckthun A (2003) Designing repeat proteins: modular leucine-rich repeat protein libraries based on the mammalian ribonuclease inhibitor family. J Mol Biol 332(2):471–487

    Article  PubMed  CAS  Google Scholar 

  • Szkudlinski MW, Fremont V, Ronin C, Weintraub BD (2002) Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships. Physiol Rev 82(2):473–502

    PubMed  CAS  Google Scholar 

  • Takeda S, Okada T, Okamura M, Haga T, Isoyama-Tanaka J, Kuwahara H, Minamino N (2004) The receptor-Galpha fusion protein as a tool for ligand screening : a model study using a nociceptin receptor-Galphai2 fusion protein. J Biochem (Tokyo) 135(5):597–604

    CAS  Google Scholar 

  • Tensen CP, Van Kesteren ER, Planta RJ, Cox KJ, Burke JF, van Heerikhuizen H, Vreugdenhil E (1994) A G protein-coupled receptor with low density lipoprotein-binding motifs suggests a role for lipoproteins in G-linked signal transduction. Proc Natl Acad Sci USA 91(11):4816–4820

    Article  PubMed  CAS  Google Scholar 

  • Vassart G, Pardo L, Costagliola S (2004) A molecular dissection of the glycoprotein hormone receptors. Trends Biochem Sci 29(3):119–126

    Article  PubMed  CAS  Google Scholar 

  • Wittamer V, Franssen JD, Vulcano M, Mirjolet JF, Le Poul E, Migeotte I, Brezillon S, Tyldesley R, Blanpain C, Detheux M, Mantovani A, Sozzani S, Vassart G, Parmentier M, Communi D (2003) Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J Exp Med 198(7):977–985

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We want to thank Dr William C Skarnes for providing us with LST20 mice and Dr Lisa Goodrich for isolating LST20 gene trap cell line. This study was supported by the Belgian State, Prime Minister’s office, Service for Sciences, Technology and Culture. Also supported by grants from FRSM, FNRS, ARBD, CICYT (SAF2002-01509) and the Improving Human Potential of the European Community (HPRI-CT-1999-00071). GVS is a fellow of the FRIA; FM is a recipient of a postdoctoral fellowship of the Francqui Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gilbert Vassart.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schoore, G.V., Mendive, F., Pochet, R. et al. Expression pattern of the orphan receptor LGR4/GPR48 gene in the mouse. Histochem Cell Biol 124, 35–50 (2005). https://doi.org/10.1007/s00418-005-0002-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-005-0002-3

Keywords

Navigation