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leucine rich repeat containing G protein-coupled receptor 4 OKDB#: 1418
 Symbols: LGR4 Species: human
 Synonyms: GPR48, BNMD17  Locus: 11p14.1 in Homo sapiens

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General Comment Multi-functional norrin is a ligand for the LGR4 receptor. Deng C et al. Mammalian LGR4, 5, and 6 are seven transmembrane receptors important for diverse physiological processes. These receptors are orthologous to DLGR2, a Drosophila receptor activated by the burs/pburs heterodimer important for morphogenesis. Although recent studies indicated that four R-spondin proteins are cognate ligands for LGR4, 5, and 6 receptors, several BMP antagonists in vertebrates have been postulated to be orthologous to burs and pburs. Based on newly available genome sequences, we now showed norrin is a vertebrate ortholog for insect burs and pburs and stimulates Wnt signaling mediated by LGR4, but not LGR5 and 6, in mammalian cells. Although norrin could only activate LGR4, binding studies suggested interactions between norrin and LGR4, 5, and 6. Norrin, the Norrie disease gene product, is also capable of activating Wnt signaling mediated by the Frizzled4 receptor and serves as a BMP antagonist. Mutagenesis studies indicated that different norrin mutations found in patients with Norrie disease can be categorized into subgroups showing defects for signaling through the three distinct binding proteins. Thus, norrin is a rare ligand capable of binding three receptors/binding proteins important for BMP and Wnt signaling pathways. Differential activities and mechanisms of the four R-Spondins in potentiating Wnt/β-catenin signaling. Park S et al. (2018) The four R-spondins (RSPO1-4) strongly potentiate Wnt signaling and play critical roles in normal development, adult stem cell survival, and cancer development and aggressiveness. All four RSPOs have been suggested to potentiate Wnt signaling by binding to three related receptors, i.e., leucine-rich repeat containing, G protein-coupled receptors 4, 5 and 6 (LGR4/5/6), and then inducing the clearance of two E3 ubiquitin ligases (RNF43 and ZNRF3) that otherwise would ubiquitinate Wnt receptors for degradation. Here we show that RSPO1-4 have differential dependence on LGRs in potentiating Wnt/β-catenin signaling and that RSPO2 can enhance this pathway without any LGR. LGR4 knockout (LGR4KO) in HEK293 cells completely abrogated Wnt/β-catenin signaling response to RSPO1 and RSPO4 and strongly impaired response to RSPO3. RSPO2, however, retained robust activity albeit with decreased potency. Complete rescue of RSPO1-4 activity in LGR4KO cells required the seven transmembrane domain of LGR4. Furthermore, an RSPO2 mutant with normal binding affinity to ZNRF3 but no or little binding to LGR4 or LGR5 still potentiated Wnt/β-catenin signaling in vitro, supported the growth of intestinal organoids ex vivo, and stimulated intestinal crypt growth in vivo. Mechanistically, RSPO2 could increase Wnt receptor levels in the absence of any LGR without affecting ZNRF3 endocytosis and stability. These findings suggest that RSPO1-4 use distinct mechanisms in regulating Wnt and other signaling pathways, which have important implications for understanding the pleiotropic functions of RSPOs and LGRs in both normal and cancer development.////////////////// LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption. Luo J et al. (2016) Tumor necrosis factor (TNF) superfamily member 11 (TNFSF11, also known as RANKL) regulates multiple physiological or pathological functions, including osteoclast differentiation and osteoporosis. TNFRSF11A (also called RANK) is considered to be the sole receptor for RANKL. Herein we report that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL. LGR4 competes with RANK to bind RANKL and suppresses canonical RANK signaling during osteoclast differentiation. RANKL binding to LGR4 activates the Gαq and GSK3-β signaling pathway, an action that suppresses the expression and activity of nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATC1) during osteoclastogenesis. Both whole-body (Lgr4(-/-)) and monocyte conditional knockout mice of Lgr4 (Lgr4 CKO) exhibit osteoclast hyperactivation (including elevation of osteoclast number, surface area, and size) and increased bone erosion. The soluble LGR4 extracellular domain (ECD) binds RANKL and inhibits osteoclast differentiation in vivo. Moreover, LGR4-ECD therapeutically abrogated RANKL-induced bone loss in three mouse models of osteoporosis. Therefore, LGR4 acts as a second RANKL receptor that negatively regulates osteoclast differentiation and bone resorption.////////////////// R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/{beta}-catenin signaling. Carmon KS et al. The Wnt/?catenin signaling system plays essential roles in embryonic development and in the self-renewal and maintenance of adult stem cells. R-spondins (RSPOs) are a group of secreted proteins that enhance Wnt/?catenin signaling and have pleiotropic functions in development and stem cell growth. LGR5, an orphan receptor of the G protein-coupled receptor (GPCR) superfamily, is specifically expressed in stem cells of the intestinal crypt and hair follicle. Knockout of LGR5 in the mouse results in neonatal lethality. LGR4, a receptor closely related to LGR5, also has essential roles in development, as its knockout leads to reduced viability and retarded growth. Overexpression of both receptors has been reported in several types of cancer. Here we demonstrate that LGR4 and LGR5 bind the R-spondins with high affinity and mediate the potentiation of Wnt/?catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. Interestingly, neither receptor is coupled to heterotrimeric G proteins or to ?arrestin when stimulated by the R-spondins, indicating a unique mechanism of action. The findings provide a basis for stem cell-specific effects of Wnt/?catenin signaling and for the broad range of functions LGR4, LGR5, and the R-spondins have in normal and malignant growth. Hsu SY, et al 1998 reported the characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. The receptors for LH, FSH, and TSH belong to the large G protein-coupled, seven-transmembrane (TM) protein family and are unique in having a large N-terminal extracellular (ecto-) domain containing leucine-rich repeats important for interaction with the glycoprotein ligands. The authors have identified two orphan leucine-rich repeat-containing, G protein-coupled receptors and named them as LGR4 and LGR5, respectively. The ectodomains of both receptors contain 17 leucine-rich repeats together with N- and C-terminal flanking cysteine-rich sequences, compared with 9 repeats found in known glycoprotein hormone receptors. The leucine-rich repeats in LGR4 and LGR5 are arrays of 24 amino acids showing similarity to repeats found in the acid labile subunit of the insulin-like growth factor (IGF)/IGF binding protein complexes as well as slit, decorin, and Toll proteins. The TM region and the junction between ectodomain and TM 1 are highly conserved in LGR4, LGR5, and seven other LGRs from sea anemone, fly, nematode, mollusk, and mammal, suggesting their common evolutionary origin. In contrast to the restricted tissue expression of gonadotropin and TSH receptors in gonads and thyroid, respectively, LGR4 is expressed in diverse tissues including ovary, testis, adrenal, placenta, thymus, spinal cord, and thyroid, whereas LGR5 is found in muscle, placenta, spinal cord, and brain. Hybridization analysis of genomic DNA indicated that LGR4 and LGR5 genes are conserved in mammals. Comparison of overall amino acid sequences indicated that LGR4 and LGR5 are closely related to each other but diverge, during evolution, from the homologous receptor found in snail and the mammalian glycoprotein hormone receptors. The identification and characterization of new members of the LGR subfamily of receptor genes not only allow future isolation of their ligands and understanding of their physiological roles but also reveal the evolutionary relationship of G protein-coupled receptors with leucine-rich repeats.//////Lgr4/Gpr48 Inactivation Leads to Aniridia-Genitourinary Anomalies-Mental Retardation Syndrome Defects. Yi T 2014 et al. AGR syndrome (the clinical triad of Aniridia, Genitourinary anomalies and mental Retardation, a subgroup of WAGR syndrome for Wilms tumor, Aniridia, Genitourinary anomalies and mental Retardation) is a rare syndrome caused by a contiguous gene deletion in the 11p13-14 region. However, the mechanisms of WAGR syndrome pathogenesis are elusive. In this study, we provide evidence that LGR4 (also named GPR48), the only G-protein coupled receptor (GPCR) gene in the human chromosome 11p12-11p14.4 fragment, is the key gene responsible for the diseases of AGR syndrome. Deletion of Lgr4 in mouse led to aniridia, polycystic kidney disease, genitourinary anomalies, and mental retardation, similar to the pathological defects of AGR syndrome. Furthermore, Lgr4 inactivation significantly increased cell apoptosis and decreased the expression of multiple important genes involved in the development of WAGR syndrome related organs. Specifically, deletion of Lgr4 down-regulated the expression of histone demethylases Jmjd2a and Fbxl10 through cAMP-CREB signaling pathways both in mouse embryonic fibroblast cells and in urinary and reproductive system mouse tissues. Our data suggest that Lgr4, which regulates eye, kidney, testis, ovary, and uterine organ development as well as mental development through genetic and epigenetic surveillance, is a novel candidate gene for the pathogenesis of AGR syndrome. /////////////////////////

NCBI Summary: The protein encoded by this gene is a G-protein coupled receptor that binds R-spondins and activates the Wnt signaling pathway. This Wnt signaling pathway activation is necessary for proper development of many organs of the body. [provided by RefSeq, Oct 2016]
General function Receptor
Comment Complex Structure of LGR4 and Rspo1: Insights into the Divergent Mechanisms of Ligand Recognition by LGR Receptors. Xu JG et al. (2014) Leucine-rich repeat G-protein-coupled receptors (LGRs) are a unique class of GPCRs characterized by a large extracellular domain to recognize ligands and regulate many important developmental processes. Among the three groups of LGRs, group B members (LGR4-6) recognize R-spondin family proteins (Rspo1-4) to stimulate Wnt signaling. In this study, we successfully utilized the hybrid LRR technique, which fused LGR4 with the hagfish VLR protein, to obtain two recombinant human LGR4 proteins: LGR415 and LGR49. We determined the crystal structures of ligand-free LGR415 and the LGR49-Rspo1 complex. LGR4 exhibits a twisted horseshoe-like structure. Rspo1 adopts a flat and β-fold architecture, and is bound in the concave surface of LGR4 in the complex through electrostatic and hydrophobic interactions. All the Rspo1-binding residues are conserved in LGR4-6, suggesting that LGR4-6 bind R-spondins through an identical surface. Structural analysis of our LGR4-Rspo1 complex with the previously determined LGR4 and LGR5 structures revealed that the concave surface of LGR4 is the sole binding site for R-spondins, suggesting a one-site binding model of LGR4-6 in ligand recognition. The molecular mechanism of LGR4-6 is distinct from the two-step mechanism of group A receptors LGR1-3 and the multiple-interface binding model of group C receptors LGR7-8, suggesting LGR receptors utilize the divergent mechanisms for ligand recognition. Our structures, together with previous reports, provide a comprehensive understanding of the ligand recognition by LGR receptors.//////////////////
Cellular localization Plasma membrane
Ovarian function Preantral follicle growth, Antral follicle growth, Luteinization, Early embryo development
Comment Oocyte-derived R-spondin2 promotes ovarian follicle development. Cheng Y et al. R-spondin proteins are adult stem cell growth factors capable of stimulating gut development by activating LGR4, 5, and 6 receptors to promote Wnt signaling. Although multiple Wnt ligands and cognate Frizzled receptors are expressed in the ovary, their physiological roles are unclear. Based on bioinformatic and in situ hybridization analyses, we demonstrated the exclusive expression of R-spondin2 in oocytes of ovarian follicles. In cultured somatic cells from preantral follicles, R-spondin2 treatment (ED(50): 3 ng/ml) synergized with Wnt3a to stimulate Wnt signaling. In cultured ovarian explants from prepubertal mice containing preantral follicles, treatment with R-spondin2, similar to follicle stimulating hormone, promoted the development of primary follicles to the secondary stage. In vivo administration of an R-spondin agonist stimulated the development of primary follicles to the antral stage in both immature mice and gonadotropin releasing hormone antagonist-treated adult mice. Subsequent treatment with gonadotropins allowed the generation of mature oocytes capable of undergoing early embryonic development and successful pregnancy. Furthermore, R-spondin agonist treatment of immune-deficient mice grafted with human cortical fragments stimulated the development of primary follicles to the secondary stage. Thus, oocyte-derived R-spondin2 is a paracrine factor essential for primary follicle development, and R-spondin agonists could provide a new treatment regimen for infertile women with low responses to the traditional gonadotropin therapy.-Cheng, Y., Kawamura, K., Takae, S., Deguchi, M., Yang, Q., Kuo, C., Hsueh, A. J. W. Oocyte-derived R-spondin2 promotes ovarian follicle development.
Expression regulated by LH
Comment Gene expression decreased. Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression. Agca C et al. The LH surge initiates the luteinization of preovulatory follicles and causes hormonal and structural changes that ultimately lead to ovulation and the formation of corpora lutea. The objective of the study was to examine gene expression in ovarian follicles (n = 11) collected from pigs (Sus scrofa domestica) approaching estrus (estrogenic preovulatory follicle; n = 6 follicles from two sows) and in ovarian follicles collected from pigs on the second day of estrus (preovulatory follicles that were luteinized but had not ovulated; n = 5 follicles from two sows). The follicular status within each follicle was confirmed by follicular fluid analyses of estradiol and progesterone ratios. Microarrays were made from expressed sequence tags that were isolated from cDNA libraries of porcine ovary. Gene expression was measured by hybridization of fluorescently labeled cDNA (preovulatory estrogenic or -luteinized) to the microarray. Microarray analyses detected 107 and 43 genes whose expression was decreased or increased (respectively) during the transition from preovulatory estrogenic to -luteinized (P<0.01). Cells within preovulatory estrogenic follicles had a gene-expression profile of proliferative and metabolically active cells that were responding to oxidative stress. Cells within preovulatory luteinized follicles had a gene-expression profile of nonproliferative and migratory cells with angiogenic properties. Approximately, 40% of the discovered genes had unknown function.
Ovarian localization Primordial Germ Cell, Oocyte, Granulosa
Comment Analysis of LGR4 receptor distribution in human and mouse tissues. Yi J 2013 et al. LGR4 is an R-spondin receptor with strong positive effect on Wnt signaling. It plays a critical role in development as its ablation in the mouse led to total embryonic/neonatal lethality with profound defects in multiple organs. Haplotype insufficiency of LGR4 in human was associated with several diseases, including increased risk of squamous cell carcinoma of the skin, reduced birth weights, electrolyte imbalance, and decreased levels of testosterone, which are similar to the phenotypes of LGR4-hypomorphic mice. Tissue distribution of LGR4 was extensively analyzed in the mouse using gene-trap reporter enzyme alleles. However, its expression pattern in human tissues remained largely unknown. We have developed LGR4-specific monoclonal antibodies and used them to examine the expression of LGR4 in selected adult human and mouse tissues by immunohistochemical analysis. Intense LGR4-like immunoreactivity was observed in the epidermis and hair follicle of the skin, pancreatic islet cells, and epithelial cells in both the male and female reproductive organs. Of particular interest is that LGR4 is highly expressed in germ cells and pancreatic islet cells, which have important implications given the role of R-spondin-LGR4 signaling in the survival of adult stem cells. In addition, the majority of colon tumors showed elevated levels of LGR4 receptor. Overall, the expression pattern of LGR4 in human tissues mapped by this IHC analysis is similar to that in the mouse as revealed from gene trap alleles. Importantly, the pattern lends strong support to the important role of LGR4 in the development and maintenance of skin, kidney, reproductive systems, and other organs. ....n the ovary, intense LGR4-IR was only found in oocyte? of primordial and primary follicles (Figure 3A-B). Interestingly, RSPO2 was recently reported to stimulate the development of primary follicles in the mouse ///////////////////////// Expression pattern of the orphan receptor LGR4/GPR48 gene in the mouse. Histochem Cell Biol. 2005 .
Follicle stages
Comment Hsu SY, et al 1998 reported that LGR4 was found in the ovary and other tissues by RT-PCR.
Mutations 4 mutations

Species: mouse
Mutation name: None
type: targeted overexpression
fertility: embryonic lethal
Comment: LGR4 receptor null mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality Mazerbourg S, et al . Leucine-rich repeat-containing, G protein-coupled receptors (LGRs) belong to the largest mammalian superfamily of proteins with seven transmembrane domains. LGRs can be divided into three subgroups based on their unique domain arrangement. Although two subgroups have been found to be receptors for glycoprotein hormones and relaxin-related ligands, respectively, the third LGR subgroup, consisting of LGR4-6, are orphan receptors with unknown physiological roles. To elucidate the functions of this subgroup of LGRs, LGR4 null mice were generated using a secretory trap approach to delete the majority of the LGR4 gene after the insertion of a beta-galactosidase reporter gene immediately after exon 1. Tissues expressing LGR4 were analyzed based on histochemical staining of the transgene driven by the endogenous LGR4 promoter. LGR4 was widely expressed in kidney, adrenal gland, stomach, intestine, heart, bone/cartilage, and other tissues. The expression of LGR4 in these tissues was further confirmed by immunohistochemical studies in wild-type animals. Analysis of the viability of 250 newborn animals suggested a skewed inheritance pattern, indicating that only 40% of the expected LGR4 null mice were born. For the LGR4 null mice viable at birth, most of them died within two days. Furthermore, the LGR4 null mice showed intrauterine growth retardation as reflected by a 14% decrease in body weight at birth, together with 30% and 40% decreases in kidney and liver weights, respectively. The present findings demonstrated the widespread expression of LGR4, an essential role of LGR4 for embryonic growth as well as kidney and liver development. The observed pre- and postnatal lethality of LGR4 null mice underlies the importance of the LGR4 signaling system for the survival and growth of animals during the perinatal stage.

Species: mouse
Mutation name: None
type: null mutation
fertility: embryonic lethal
Comment: Reduced fertility with impairment of early-stage embryos observed in mice lacking Lgr4 in epithelial tissues. Mohri Y et al. Lgr4 is one of the genes identified as novel G protein-coupled receptor genes designated Lgr4-Lgr8, with high homology with FSH receptor, LH receptor, and TSH receptor genes, but studies of Lgr4-mutant mice have suggested that Lgr4 has essential functions in development. This is the first report describing the relationship between the functions of Lgr4 and female reproductive systems.

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. Styrkarsdottir U et al. Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice.

Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Lgr4 gene regulates Corpus Luteum Maturation through Modulation of the WNT mediated EGFR-ERK Signaling Pathway. Pan H 2014 et al. Luteal phase insufficiency is one of the major causes of female infertility, but the molecular mechanisms are still largely unknown. Here we found that disruption of LGR4/GPR48, the newly identified receptor for R-spondins, greatly reduced female fertility in mice. The expression of Lgr4 was induced specifically in granulosa-lutein cells during luteinization. In Lgr4 deficient female mice, the estrous cycle was prolonged and serum progesterone levels were dramatically downregulated. In Lgr4(-/-) corpora lutea, the expression of key enzymes for steroidogenesis as well as common luteal marker genes was significantly decreased. Additionally, the activity of EGFR-ERK signaling was attenuated in Lgr4(-/-) granulosa-lutein cells. We found that the maturation of Lgr4(-/-) cells was impaired in cultured primary granulosa cells, but the defect was partially rescued by reactivation of EGFR signaling by HB-EGF treatment. We found that the expression of WNT/CTNNB1 downstream targets, including MMP9 which is a critical matrix metalloproteinase for activation of EGF-like factors, was significantly downregulated in Lgr4(-/-) ovaries. MMP9 inhibitor treatment attenuated hCG but not HB-EGF induced ERK activation and luteinization in primary granulosa cells. Together, we report that Lgr4 modulates WNT mediated EGFR-ERK signaling to facilitate corpus luteum maturation and ovarian steroidogenesis to maintain female reproduction. /////////////////////////

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created: Jan. 18, 2002, 9:22 a.m. by: hsueh   email:
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last update: May 15, 2018, 9:12 a.m. by: hsueh    email:

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