Affinage

RSPO1

R-spondin-1 · UniProt Q2MKA7

Length
263 aa
Mass
29.0 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RSPO1 is a secreted Wnt signaling potentiator that functions as a ligand bridging LGR4/5/6 receptors and the transmembrane E3 ubiquitin ligases ZNRF3/RNF43, forming a ternary complex that clears ZNRF3/RNF43 from the cell surface and thereby stabilizes Frizzled receptors to amplify canonical β-catenin signaling. Structural studies show that the RSPO1 Fu1 domain hairpin inserts into a groove on ZNRF3/RNF43 ectodomains while the Fu2 domain contacts the concave LRR surface of LGR4/5/6, with LGR serving as an engagement receptor that increases RSPO1 affinity for the effector receptor RNF43/ZNRF3; signaling potency is determined by the strength of ternary complex formation (PMID:24225776, PMID:23756651, PMID:25504990). RSPO1 activates β-catenin signaling in XX gonads to drive ovarian differentiation, germ cell meiosis entry, and female sex determination, with Rspo1 knockout mice exhibiting masculinized gonads and loss of Wnt4 activation (PMID:18250098, PMID:21991325). Beyond gonadal development, RSPO1 functions in intestinal stem cell self-renewal distinct from but cooperative with Wnt ligands, promotes angiogenesis through a Wnt-Vegfc-Vegfr3 axis in zebrafish, maintains nephron progenitors redundantly with RSPO3, and regulates energy homeostasis via LGR4 signaling in adipocytes and hypothalamic neurons (PMID:28467820, PMID:22007135, PMID:32324134, PMID:36755192).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2008 High

    Establishing that RSPO1 is a Wnt/β-catenin pathway amplifier: the furin-like cysteine-rich domains were shown to be both necessary and sufficient for potentiating multiple Wnt ligands and antagonizing DKK1, defining RSPO1 as a synergistic enhancer rather than an independent signaling ligand.

    Evidence Systematic domain deletion analysis with TOPFLASH reporter assays and DKK1 antagonism in mammalian cells across all four RSPO family members

    PMID:18400942

    Open questions at the time
    • Receptor identity unknown
    • Mechanism of DKK1 antagonism unresolved at molecular level
    • No structural information on furin domains
  2. 2008 High

    Demonstrating RSPO1's essential role in female sex determination: Rspo1 knockout revealed that RSPO1-dependent β-catenin activation in XX gonads controls Wnt4 expression, ovarian differentiation, and germ cell meiosis entry, establishing a non-redundant developmental function.

    Evidence Rspo1 knockout mice with histology, Wnt4 expression analysis, and germ cell meiosis markers

    PMID:18250098

    Open questions at the time
    • Cell-autonomous vs. paracrine role in gonad not fully resolved
    • Downstream target gene network not characterized
  3. 2010 Medium

    Extending RSPO1 function to bone homeostasis: RSPO1 was shown to promote osteoblast differentiation through Wnt activation and DKK1 antagonism, while inhibiting osteoclastogenesis via OPG induction, providing the first evidence of RSPO1 in adult tissue protection.

    Evidence In vivo treatment of TNFα-transgenic arthritis mice combined with in vitro osteoblast Wnt signaling and osteoclastogenesis assays

    PMID:20506554

    Open questions at the time
    • Direct receptor on osteoblasts not identified
    • Whether effect is direct or paracrine not resolved
    • Single lab finding
  4. 2011 High

    Identification of LGR4/5/6 as the cognate receptors for R-spondins resolved a central question of how RSPO1 signals; three independent studies demonstrated that RSPO1 binds LGR4/5 extracellular domains and that LGR4 is required for RSPO1-mediated Wnt enhancement, with clathrin-mediated endocytosis as the downstream internalization route.

    Evidence Mass spectrometry, co-immunoprecipitation, genome-wide siRNA screen, direct binding assays to LGR4/5 ECDs, Lgr4-/- intestinal crypts, and endocytosis inhibitor experiments in mammalian cells and Xenopus

    PMID:21727895 PMID:21909076 PMID:22815884

    Open questions at the time
    • No G-protein coupling detected — downstream intracellular mechanism unclear
    • Structural basis of RSPO-LGR interaction unknown
    • ZNRF3/RNF43 connection not yet established
  5. 2011 High

    Establishing developmental roles beyond the gonad: RSPO1 was shown to be required for angiogenesis in zebrafish through a Wnt-Vegfc-Vegfr3 axis and to promote germ cell meiosis via cell-autonomous β-catenin activation, while also enhancing myogenesis through Wnt/β-catenin-dependent MYF5 induction.

    Evidence Zebrafish forward-genetic screen with epistasis analysis, Rspo1 KO mouse germ cell analysis, and C2C12/primary satellite cell assays with dominant-negative constructs

    PMID:21252233 PMID:21991325 PMID:22007135

    Open questions at the time
    • Receptor identity in endothelial cells not tested
    • Relative contribution of RSPO1 vs. other RSPOs in each tissue unclear
  6. 2012 High

    Genetic epistasis revealed that RSPO1 and WNT4 cooperatively drive gonadal cell proliferation regardless of sex, with double knockout causing hypoplastic testes due to coelomic epithelium failure, establishing RSPO1 as a sex-independent growth factor in early gonad development.

    Evidence Double Rspo1/Wnt4 mouse knockout with histology, cell proliferation, and lineage analysis

    PMID:23095882

    Open questions at the time
    • Molecular mechanism of RSPO1-WNT4 synergy not defined
    • Whether LGR receptors mediate this effect unknown
  7. 2013 High

    A burst of crystallographic studies resolved the atomic mechanism: RSPO1 Fu1 hairpin inserts into ZNRF3/RNF43, Fu2 contacts the concave LRR surface of LGR4/5, and RSPO1 is sandwiched between LGR5 and RNF43 in a ternary complex where LGR enhances RSPO affinity for ZNRF3/RNF43; this established the dual-receptor model with LGR as engagement receptor and ZNRF3/RNF43 as effector receptor whose membrane clearance activates Wnt signaling.

    Evidence Multiple crystal structures (RSPO1-LGR5, RSPO1-LGR4, RSPO1-ZNRF3, RSPO1-LGR5-RNF43 ternary, ZNRF3-RSPO2), in vitro reconstitution of ternary complexes, mutagenesis, binding affinity measurements, membrane clearance assays, and disease mutation mapping

    PMID:23756651 PMID:23756652 PMID:23809763 PMID:24050775 PMID:24165923 PMID:24225776 PMID:24349440

    Open questions at the time
    • Full-length receptor complex structure lacking
    • Mechanism of ZNRF3 internalization upon RSPO binding not structurally resolved
    • Stoichiometry differences between ZNRF3 (2:2:2) and RNF43 (1:1:1) complexes not explained mechanistically
  8. 2014 High

    Quantitative analysis of all four RSPOs demonstrated that signaling potency is determined by ternary complex affinity: engineering a chimeric 'Superspondin' combining the strongest ZNRF3-binding (RSPO2) and LGR4-binding (RSPO4) domains produced 10-fold enhanced potency, providing a pharmacological framework for RSPO therapeutics.

    Evidence Purified protein binding assays, Wnt reporter assays, chimeric protein engineering, and crystal structure of LGR4-RSPO1 defining one-site binding model

    PMID:25480784 PMID:25504990

    Open questions at the time
    • In vivo potency of Superspondin not tested
    • Whether enhanced potency alters tissue specificity unknown
  9. 2017 High

    A critical conceptual advance established that RSPO and Wnt ligands are non-interchangeable: Wnt maintains RSPO receptor expression but cannot drive stem cell self-renewal alone, while RSPO actively expands Lgr5+ intestinal stem cells, redefining the Wnt/RSPO hierarchy in stem cell biology.

    Evidence Mouse genetics, organoid cultures with non-lipidated Wnt analogue, RSPO gain-of-function, and in vivo Lgr5+ ISC analysis

    PMID:28467820

    Open questions at the time
    • Whether this hierarchy applies in non-intestinal stem cell compartments unknown
    • Downstream transcriptional targets distinguishing RSPO vs. Wnt effects not fully characterized
  10. 2020 High

    Tissue-specific RSPO1/3 double knockout in nephron progenitors revealed functional redundancy between RSPO1 and RSPO3 and, unexpectedly, that LGR4/5/6 triple deletion only mildly affected progenitor maintenance, demonstrating an LGR-independent RSPO signaling mode involving BMP7-SMAD1/5 pathway activation.

    Evidence Mouse conditional knockouts (RSPO1/3 single and double, LGR4/5/6 triple), SMAD phosphorylation assays, and molecular marker analysis

    PMID:32324134

    Open questions at the time
    • Identity of the LGR-independent RSPO receptor unknown
    • Mechanism linking RSPO to BMP7/SMAD signaling not resolved
    • Whether LGR-independent signaling occurs in other tissues untested
  11. 2020 Medium

    RSPO1 was shown to regulate metabolic processes beyond development: it inhibits beige adipocyte thermogenesis via LGR4-Wnt/β-catenin signaling, with a gain-of-function R219W mutation disrupting extracellular matrix retention and causing excessive RSPO1 release, and it suppresses hepatic cholesterol synthesis through an LGR4-AMPKα-SREBP2 axis.

    Evidence Mouse knockout/overexpression/knockin models (R219W), mitochondrial respiration assays, AMPKα epistasis experiments, and SREBP2 nuclear translocation assays

    PMID:32926477 PMID:36755192

    Open questions at the time
    • Whether AMPKα activation is direct or indirect through Wnt/β-catenin not resolved
    • Physiological RSPO1 concentrations in circulation unknown
    • Hepatic and adipose findings from different groups, not yet integrated
  12. 2023 Medium

    Mechanistic refinement showed that LGR4, but not LGR5, pre-associates with RNF43/ZNRF3 to provide high-affinity bivalent RSPO binding via a 2:2 dimer, explaining differential signaling capacity between LGR4 and LGR5 contexts.

    Evidence Whole-cell binding assays with monovalent and bivalent RSPO2 ligands, co-expression experiments, and affinity measurements

    PMID:37402772

    Open questions at the time
    • Structural basis of LGR4-ZNRF3 pre-association not resolved
    • In vivo relevance of differential LGR4 vs. LGR5 complex formation untested
    • Single lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of LGR-independent RSPO receptors in nephron progenitors and potentially other tissues, the structural basis of full-length ternary receptor complexes in a membrane context, and the mechanisms governing tissue-specific RSPO1 signaling outcomes (e.g., stem cell expansion vs. metabolic regulation vs. developmental fate decisions).
  • LGR-independent receptor identity unknown
  • No full-length membrane-embedded complex structure
  • Tissue-specific signaling logic not mechanistically explained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 4 GO:0031012 extracellular matrix 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1430728 Metabolism 2
Partners
LGR4LGR5LGR6RNF43WNT4ZNRF3
Complex memberships
RSPO1-LGR4/5-ZNRF3/RNF43 ternary complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 LGR4 and LGR5 associate with the Frizzled/LRP Wnt receptor complex and act as receptors for all four R-spondins; RSPO1 enhances canonical WNT3A signaling in HEK293 cells in an LGR4-dependent manner, and removal of LGR4 abrogates RSPO1-mediated signal enhancement, which is rescued by re-expression of LGR4, LGR5, or LGR6. Mass spectrometry, co-immunoprecipitation, HEK293 cell signaling assays, conditional mouse knockout, intestinal crypt cultures Nature High 21727895
2011 R-spondins bind to orphan GPCRs LGR4 and LGR5 through their Furin domains; LGR4/LGR5 promote R-spondin-mediated Wnt/β-catenin signaling, and R-spondin-triggered β-catenin signaling requires Clathrin-mediated endocytosis (distinct from Caveolin-dependent Wnt3a signaling). Gain- and loss-of-function in mammalian cells and Xenopus embryos, binding assays, endocytosis inhibitors EMBO reports High 21909076
2008 RSPO1 activates canonical β-catenin signaling in XX gonads to control ovarian differentiation; Rspo1 knockout mice show masculinized gonads, absence of female-specific Wnt4 activation, XY-like vascularization and steroidogenesis, and failure of germ cells to enter meiosis. Mouse knockout, molecular analyses of Wnt4 expression, histology, germ cell analysis Human molecular genetics High 18250098
2008 All four RSpo family members require Wnt ligands and LRP6 for activity, amplify signaling of multiple Wnt ligands (Wnt3A, Wnt1, Wnt7A), and antagonize DKK1 by interfering with DKK1-mediated LRP6/Kremen association; the furin-like cysteine-rich domains are sufficient and essential for Wnt signal amplification and DKK1 inhibition. TOPFLASH reporter assays, deletion mutant analysis, DKK1 antagonism assays, mammalian cell transfection Molecular biology of the cell High 18400942
2013 Crystal structures of ZNRF3 ectodomain and its complex with Rspo2 Fu1-Fu2 reveal that a prominent loop in Fu1 clamps into a groove in ZNRF3(ecto)/RNF43(ecto); RSPO binding enhances dimerization of ZNRF3(ecto); signaling potency depends on ability to recruit ZNRF3 or RNF43 via Fu1 into a ternary complex with LGR receptors (which interact via Fu2), establishing LGR5 as engagement receptor and RNF43 as effector receptor. Multiple crystal structures (ZNRF3 ecto, Rspo2-Fu1-Fu2, complexes with ZNRF3 and RNF43), biophysical assays, cellular signaling assays, mutagenesis Nature communications High 24225776
2013 Crystal structure of RSPO1 bound simultaneously to LGR5 and RNF43 ectodomains shows RSPO1 sandwiched between them: the rod module of the cysteine-rich domain contacts LGR5 and a hairpin is inserted into RNF43; LGR5 does not contact RNF43 but increases affinity of RSPO1 for RNF43; disease mutations map to the RSPO1-RNF43 interface. Crystal structure (X-ray), binding affinity measurements, disease mutation mapping Genes & development High 23756651
2013 Crystal structure of the LGR4 extracellular domain with RSPO1 N-terminal fragment (Fu-CRD1 and Fu-CRD2) shows LGR4 adopts a twisted horseshoe structure; both FU-CRD1 and FU-CRD2 contribute to LGR4 binding; all RSPO1-binding residues are conserved in LGR4-6, explaining promiscuous binding. Crystal structure determination, binding assays, cellular signaling assays, mutational analysis Genes & development High 23756652
2013 Crystal structure of R-spondin 1 and its complex with LGR5 ectodomain at 3.2 Å; ecto-LGR5 binds Rspo1 at its concave LRR surface forming a dimeric 2:2 complex; a phenylalanine clamp formed by Rspo1 Phe106 and Phe110 pinching Ala190 of LGR5 is critical for binding; anonychia-related mutations reduce signaling but not binding. Crystal structure (2.0 Å Rspo1 alone, 3.2 Å Rspo1-LGR5 complex), mutagenesis, binding assays, signaling assays Cell reports High 23809763
2013 R-spondin interacts with ZNRF3/RNF43 and LGR4 through distinct motifs; both LGR4 and ZNRF3 binding motifs are required for R-spondin-induced LGR4/ZNRF3 interaction, membrane clearance of ZNRF3, and Wnt signaling activation; R-spondin primarily functions by binding and inhibiting ZNRF3 (dual receptor model: LGR4/5 as engagement receptor, ZNRF3/RNF43 as effector receptor). Co-immunoprecipitation, siRNA knockdown, mutational analysis of R-spondin, ZNRF3 membrane clearance assays, Wnt signaling reporter assays EMBO reports High 24165923
2012 LGR4 identified by unbiased siRNA screen as the cognate receptor of RSPO; depletion of LGR4 abolishes RSPO-induced β-catenin signaling; RSPO binds to the extracellular domain of LGR4 and LGR5; overexpression of LGR4 sensitizes cells to RSPO signaling; no G-protein coupling detected, indicating novel mechanism. Genome-wide siRNA screen, direct binding assays to LGR4/5 ECD, β-catenin reporter assays, G-protein coupling assays, Lgr4-/- intestinal crypt cultures PloS one High 22815884
2013 Reconstitution of RSPO:LGR4:ZNRF3 ternary complexes with bacterially-produced proteins; RSPOs bind LGR4 with nanomolar affinities (rank order RSPO4 > RSPO2 > RSPO3 > RSPO1) and ZNRF3 weakly (rank order RSPO2 > RSPO3 > RSPO1; RSPO4:ZNRF3 undetectable); stronger signaling potency of RSPO2/3 correlates with their strong binding of both receptors; LGR4 and ZNRF3 N-glycans dispensable for function. In vitro reconstitution with purified recombinant proteins, TR-FRET binding assays, native gel EMSA, Wnt signaling reporter assays Biochemistry High 24050775
2013 Structures of ZNRF3 ectodomain and its complex with RSPO1 (crystal structures); ZNRF3 binds RSPO1 via the Fu1 domain with micromolar affinity; anonychia-related RSPO4 mutations support the observed interface; ZNRF3-binding site overlaps with trans-interactions in LGR5-RSPO1 complexes, suggesting competing binding roles. Crystal structures of ZNRF3 ecto and ZNRF3-RSPO1 complex, binding affinity measurements, disease mutation mapping PloS one High 24349440
2015 Crystal structure of LGR5 complexed with Rspo2 Fu1-Fu2 shows Rspo2 engages LGR5 in a fashion almost identical to RSPO1; ternary hLGR5-mRspo2-mZNRF3 complex structure confirms Rspo proteins crosslink LGRs and ZNRF3 into a 2:2:2 complex (whereas 1:1:1 with RNF43); LGR5 ectodomains show plasticity with ~9° rotation of N-terminal half relative to C-terminal half. Crystal structure (high resolution LGR5-Rspo2 and low resolution ternary complex), structural comparison Journal of structural biology High 26123262
2014 Crystal structure of LGR4-Rspo1 complex defines the concave surface of LGR4 as the sole binding site for R-spondins (one-site binding model); Rspo1 adopts a flat β-fold architecture; all Rspo1-binding residues are conserved in LGR4-6; mechanism is distinct from group A LGR1-3 (two-step) and group C LGR7-8 (multiple interface) receptors. Crystal structure determination (LGR4 alone and LGR4-Rspo1 complex), binding assays, cellular signaling assays The Journal of biological chemistry High 25480784
2014 Signaling potency of RSPOs1-4 is determined by their ability to form ternary complexes with LGR4 and ZNRF3; RSPO2 has stronger ZNRF3 binding than RSPO1; engineering a chimeric 'Superspondin' (RSPO2 ZNRF3-binding + RSPO4 LGR4-binding) produces 10-fold stronger potency than RSPO2; RSPO efficacy depends on ZNRF3 recruitment. In vitro binding assays (purified proteins), Wnt signaling reporter assays, chimeric protein engineering, mutagenesis Molecular pharmacology High 25504990
2017 RSPO ligands and Wnt ligands have qualitatively distinct, non-interchangeable roles in intestinal stem cells: Wnt proteins cannot induce Lgr5+ ISC self-renewal but maintain RSPO receptor expression, while RSPO ligands actively drive stem-cell expansion; the default fate of Lgr5+ ISCs is to differentiate unless both are present. Mouse genetics, organoid cultures, non-lipidated Wnt analogue, RSPO gain-of-function, in vivo analysis of Lgr5+ ISCs Nature High 28467820
2011 RSPO1 activates the WNT/β-catenin signaling pathway in germ cells of XX gonads to promote oogonial differentiation and entry into meiosis; in Rspo1(-/-) XX gonads, germ cell proliferation, Stra8 expression, and meiosis entry are impaired prior to Sertoli cell differentiation, indicating β-catenin acts within germ cells. Mouse knockout, immunostaining, meiotic marker analysis, genetic epistasis PloS one High 21991325
2012 RSPO1 and WNT4 together are required for cell proliferation in the early gonad regardless of sex; simultaneous ablation of Rspo1 and Wnt4 impairs proliferation of coelomic epithelium cells in XY gonads, reducing Sertoli cell progenitor numbers and resulting in hypoplastic testes. Double mouse knockout (Rspo1-/-; Wnt4-/-), histology, cell proliferation analysis, lineage analysis Development (Cambridge, England) High 23095882
2011 In zebrafish, Rspo1 promotes angiogenesis through a Rspo1-Wnt-Vegfc-Vegfr3 signaling axis; rspo1 mutants fail in angiogenesis (not vasculogenesis), Vegfc expression is Rspo1/Wnt-dependent, and Vegfc/Vegfr3 are necessary downstream effectors; endothelial-autonomous canonical Wnt inhibition blocks angiogenesis. Zebrafish forward-genetic screen, morpholino knockdown, endothelial-specific Wnt inhibition, epistasis analysis Development (Cambridge, England) High 22007135
2020 RSPO1 inhibits adipocyte mitochondrial respiration and thermogenesis in beige adipocytes via LGR4-Wnt/β-catenin signaling; a gain-of-function mutation (R219W) disrupts RSPO1's electrostatic interaction with extracellular matrix, causing excessive RSPO1 release that activates LGR4-Wnt/β-catenin and attenuates thermogenic capacity. Mouse overexpression and knockout, humanized knockin mice (R219W), Wnt/β-catenin reporter assays, mitochondrial respiration assays, whole-exome sequencing in humans Advanced science (Weinheim, Baden-Wurttemberg, Germany) High 36755192
2013 Rspo1 is required for hematopoietic stem cell specification through parallel signaling pathways: Wnt16/DeltaC/DeltaD and Vegfa/Tgfβ1, acting as key upstream regulator of both pathways controlling HSC specification and ISV patterning in zebrafish. Zebrafish morpholino knockdown, genetic epistasis, rescue experiments Development (Cambridge, England) Medium 28087636
2011 R-spondins (RSPO1/2) promote skeletal myogenesis by enhancing MYF5 expression and myogenic differentiation through WNT/β-catenin signaling; DKK1 or dominant-negative TCF4 reverses RSPO2-induced effects, placing RSPOs upstream of β-catenin/TCF. Overexpression, recombinant protein treatment, siRNA knockdown, C2C12 and primary satellite cell assays, dominant-negative constructs The Journal of biological chemistry Medium 21252233
2010 RSpo1 modulates Wnt signaling in osteoblasts by antagonizing DKK-1, induces osteoblast differentiation and OPG expression (inhibiting osteoclastogenesis), and protects joints from inflammatory bone damage in TNFα-transgenic arthritis mice. TNFα-transgenic mouse treatment, histology, in vitro osteoblast Wnt signaling assays, osteoclastogenesis assays Arthritis and rheumatism Medium 20506554
2020 RSPO1 and RSPO3 act in a functionally redundant manner to permit WNT/β-catenin signaling in nephron progenitors; tissue-specific deletion in cap mesenchymal cells abolishes mesenchyme-to-epithelial transition linked to loss of Bmp7, absence of SMAD1/5 phosphorylation, and failure to activate Lef1, Fgf8, and Wnt4; LGR4/5/6 deletion only mildly affects progenitor numbers and does not interfere with MET, revealing LGR-independent RSPO functions. Mouse conditional knockout (RSPO1/3 single and double KO, LGR4/5/6 triple KO), molecular marker analysis, SMAD phosphorylation assays eLife High 32324134
2023 ROTACs: signaling-disabled RSPO2 chimeras (with WNT- and BMP-signaling mutations) exploit ZNRF3/RNF43 E3 ligase binding to target transmembrane proteins (e.g., PD-L1) for lysosomal degradation; PD-L1 degradation is strictly dependent on ZNRF3/RNF43. Bispecific chimeric protein engineering, cell-based degradation assays, ZNRF3/RNF43 dependency tests, T-cell reactivation assays Cell chemical biology Medium 37321224
2023 LGR4 but not LGR5 complexes with RNF43/ZNRF3 to provide high-affinity bivalent RSPO binding; LGR4 and RNF43/ZNRF3 form a 2:2 dimer accommodating bivalent RSPO whereas LGR5 forms a homodimer that does not interact with ZNRF3, explaining differential signaling between LGR4 and LGR5. Whole-cell binding assays with monovalent and bivalent RSPO2 ligands, co-expression experiments, affinity measurements Scientific reports Medium 37402772
2013 Rspo1 injected into the third brain ventricle inhibits food intake in rats; Rspo1 is expressed in hypothalamic VMH neurons and co-localizes with LGR4-expressing NPY and POMC neurons; Rspo1 decreases NPY and increases POMC expression in the arcuate nucleus, placing Rspo1-LGR4 as novel hypothalamic energy homeostasis circuit. In situ hybridization, ICV injection, food intake measurement, NPY/POMC mRNA analysis Endocrinology Medium 24280058
2020 RSPO1 overexpression in ApcMin/+ mice suppresses intestinal adenoma growth by initially increasing apoptosis and Wnt target gene expression in adenoma cells, followed by reduced Wnt signaling and proliferation; this effect is dependent on TGFβ/SMAD signaling, as TGFβR inhibition restores adenoma organoid growth and reverts apoptosis. AAV-RSPO1-Fc mouse model, organoid cultures, single-cell RNA sequencing, SMAD phosphorylation assays, pharmacological TGFβR inhibition Gastroenterology Medium 32941878
2019 In the mammary gland, hormones regulate Rspo1 expression via Amphiregulin (Areg) paracrine signaling: estrogen receptor-positive luminal cells produce Areg, which induces Rspo1 expression in ER-negative luminal cells in an EGFR-dependent manner, identifying an Estrogen-Areg-Rspo1 regulatory axis. Cell co-culture, siRNA knockdown, EGFR inhibition, conditioned medium experiments Developmental biology Medium 31610144
2020 Rspo1/Rspo3-LGR4 signaling in hepatocytes suppresses cholesterol synthesis via the AMPKα-SREBP2 pathway; LGR4 knockdown increases hepatic cholesterol synthesis and decreases AMPKα phosphorylation; AMPKα activation/inhibition abolishes LGR4 deficiency or Rspo effects on cholesterol synthesis. LGR4/Rspo1/3 knockdown mouse models, AMPKα shRNA/agonist/antagonist, SREBP2 nuclear translocation assays, in vitro and in vivo cholesterol synthesis measurements FASEB journal Medium 32926477
2017 Stromal R-spondin 3 produced by gastric myofibroblasts maintains Lgr5+ and Axin2+ stem cell expression in the gastric antrum; exogenous R-spondin administration expands Axin2+/Lgr5- but not Lgr5+ cells; H. pylori increases stromal Rspo3 expression to drive hyperproliferation. Lgr5+ cell depletion, exogenous R-spondin administration, Axin2-lacZ reporter, myofibroblast RSPO3 source identification, H. pylori infection model Nature High 28813421
2017 R-spondin (Rspo1) combined with Slit2 reduces intestinal stem cell loss during lethal chemoradiation, mitigates gut impairment, and protects animals from death without decreasing tumor sensitivity to chemotherapy, acting as Wnt agonist-mediated stem cell induction. Mouse lethal chemoradiation model, Rspo1 + Slit2 administration, ISC quantification, survival analysis, tumor response evaluation Nature Medium 23903657

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 1058 21727895
2012 Recurrent R-spondin fusions in colon cancer. Nature 798 22895193
2011 LGR4 and LGR5 are R-spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling. EMBO reports 473 21909076
2008 Activation of beta-catenin signaling by Rspo1 controls differentiation of the mammalian ovary. Human molecular genetics 358 18250098
2017 Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal. Nature 349 28467820
2008 R-Spondin family members regulate the Wnt pathway by a common mechanism. Molecular biology of the cell 284 18400942
2018 Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis. Cell 265 30096312
2012 The R-spondin protein family. Genome biology 233 22439850
2006 R-Spondin proteins: a novel link to beta-catenin activation. Cell cycle (Georgetown, Tex.) 215 16357527
2017 Stromal R-spondin orchestrates gastric epithelial stem cells and gland homeostasis. Nature 171 28813421
2008 R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis. Development (Cambridge, England) 166 18256198
2013 Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin. Nature communications 162 24225776
2012 R-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5. PloS one 145 22815884
2006 The gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, is mutated in inherited anonychia. Nature genetics 145 17041604
2008 The Wnt signaling regulator R-spondin 3 promotes angioblast and vascular development. Development (Cambridge, England) 140 18842812
2014 Stem cells marked by the R-spondin receptor LGR5. Gastroenterology 134 24859206
2013 Induction of intestinal stem cells by R-spondin 1 and Slit2 augments chemoradioprotection. Nature 126 23903657
2004 R-spondin, a novel gene with thrombospondin type 1 domain, was expressed in the dorsal neural tube and affected in Wnts mutants. Biochimica et biophysica acta 126 14732490
2013 The structural basis of R-spondin recognition by LGR5 and RNF43. Genes & development 124 23756651
2019 R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon. Nature communications 108 31554819
2012 The R-spondin family of proteins: emerging regulators of WNT signaling. The international journal of biochemistry & cell biology 107 22982762
2006 Dynamic expression of R-spondin family genes in mouse development. Gene expression patterns : GEP 106 17035101
2011 RSPO1/β-catenin signaling pathway regulates oogonia differentiation and entry into meiosis in the mouse fetal ovary. PloS one 102 21991325
2022 Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 in osteoarthritis. Annals of the rheumatic diseases 101 36175067
2009 Wnt11 promotes osteoblast maturation and mineralization through R-spondin 2. The Journal of biological chemistry 101 19213727
2008 Syndromic true hermaphroditism due to an R-spondin1 (RSPO1) homozygous mutation. Human mutation 101 18085567
2013 Structural basis for R-spondin recognition by LGR4/5/6 receptors. Genes & development 100 23756652
2015 Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types. Cancer research 97 26719531
2017 R-Spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine. Nature communications 95 28695896
2011 Rspo1/Wnt signaling promotes angiogenesis via Vegfc/Vegfr3. Development (Cambridge, England) 92 22007135
2011 A WNT/beta-catenin signaling activator, R-spondin, plays positive regulatory roles during skeletal myogenesis. The Journal of biological chemistry 89 21252233
2013 Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin. EMBO reports 87 24165923
2012 WNT4 and RSPO1 together are required for cell proliferation in the early mouse gonad. Development (Cambridge, England) 86 23095882
2006 Mutations in the gene encoding the Wnt-signaling component R-spondin 4 (RSPO4) cause autosomal recessive anonychia. American journal of human genetics 80 17186469
2013 Structure of stem cell growth factor R-spondin 1 in complex with the ectodomain of its receptor LGR5. Cell reports 75 23809763
2021 The role of R-spondin proteins in cancer biology. Oncogene 70 34663878
2013 R-spondin 2 signalling mediates susceptibility to fatal infectious diarrhoea. Nature communications 68 23695692
2013 Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling. PloS one 65 24349440
2011 Human RSPO1/R-spondin1 is expressed during early ovary development and augments β-catenin signaling. PloS one 65 21297984
2016 R-spondin 1 and noggin facilitate expansion of resident stem cells from non-damaged gallbladders. EMBO reports 62 26993089
2008 Genetics of ovarian differentiation: Rspo1, a major player. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 62 18987496
2013 Wnt/Rspondin/β-catenin signals control axonal sorting and lineage progression in Schwann cell development. Proceedings of the National Academy of Sciences of the United States of America 58 24151333
2025 Hepatic stellate cells control liver zonation, size and functions via R-spondin 3. Nature 57 40074890
2012 WNT4, RSPO1, and FOXL2 in sex development. Seminars in reproductive medicine 54 23044875
2016 Involvement of FOXL2 and RSPO1 in Ovarian Determination, Development, and Maintenance in Mammals. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 51 27649556
2010 R-spondin 1 protects against inflammatory bone damage during murine arthritis by modulating the Wnt pathway. Arthritis and rheumatism 51 20506554
2016 LGR4 acts as a key receptor for R-spondin 2 to promote osteogenesis through Wnt signaling pathway. Cellular signalling 50 27140682
2020 Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs. PloS one 43 32160239
2016 Dmy initiates masculinity by altering Gsdf/Sox9a2/Rspo1 expression in medaka (Oryzias latipes). Scientific reports 41 26806354
2015 Crystal structure of R-spondin 2 in complex with the ectodomains of its receptors LGR5 and ZNRF3. Journal of structural biology 41 26123262
2007 RSPO4 is the major gene in autosomal-recessive anonychia and mutations cluster in the furin-like cysteine-rich domains of the Wnt signaling ligand R-spondin 4. The Journal of investigative dermatology 40 17914448
2013 Sequence and gene content of a large fragment of a lizard sex chromosome and evaluation of candidate sex differentiating gene R-spondin 1. BMC genomics 39 24344927
2016 Rspo1-activated signalling molecules are sufficient to induce ovarian differentiation in XY medaka (Oryzias latipes). Scientific reports 38 26782368
2020 Transcriptional Profiling of the Adult Hair Follicle Mesenchyme Reveals R-spondin as a Novel Regulator of Dermal Progenitor Function. iScience 37 32289736
2007 Mutations in R-spondin 4 (RSPO4) underlie inherited anonychia. The Journal of investigative dermatology 36 17805348
2021 Role of R-spondin 2 in arterial lymphangiogenesis and atherosclerosis. Cardiovascular research 35 32750106
2020 Expression of R-Spondin 1 in ApcMin/+ Mice Suppresses Growth of Intestinal Adenomas by Altering Wnt and Transforming Growth Factor Beta Signaling. Gastroenterology 35 32941878
2019 R-spondin 2-LGR4 system regulates growth, migration and invasion, epithelial-mesenchymal transition and stem-like properties of tongue squamous cell carcinoma via Wnt/β-catenin signaling. EBioMedicine 35 31097406
2019 R-spondin signaling as a pivotal regulator of tissue development and homeostasis. The Japanese dental science review 34 31049116
2017 Evidence of the Role of R-Spondin 1 and Its Receptor Lgr4 in the Transmission of Mechanical Stimuli to Biological Signals for Bone Formation. International journal of molecular sciences 34 28272338
2013 Lmx1a encodes a rostral set of mesodiencephalic dopaminergic neurons marked by the Wnt/B-catenin signaling activator R-spondin 2. PloS one 34 24066094
2016 R-spondin 2 facilitates differentiation of proliferating chondrocytes into hypertrophic chondrocytes by enhancing Wnt/β-catenin signaling in endochondral ossification. Biochemical and biophysical research communications 32 27012200
2020 Tissue-targeted R-spondin mimetics for liver regeneration. Scientific reports 31 32811902
2020 R-Spondin 2 Induces Odontogenic Differentiation of Dental Pulp Stem/Progenitor Cells via Regulation of Wnt/β-Catenin Signaling. Frontiers in physiology 29 32848860
2023 ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation. Cell chemical biology 28 37321224
2022 Comprehensive Analysis of R-Spondin Fusions and RNF43 Mutations Implicate Novel Therapeutic Options in Colorectal Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 28 35254413
2020 R-spondin substitutes for neuronal input for taste cell regeneration in adult mice. Proceedings of the National Academy of Sciences of the United States of America 28 33443181
2016 MYC and PVT1 synergize to regulate RSPO1 levels in breast cancer. Cell cycle (Georgetown, Tex.) 27 26889781
2014 Crystal structure of LGR4-Rspo1 complex: insights into the divergent mechanisms of ligand recognition by leucine-rich repeat G-protein-coupled receptors (LGRs). The Journal of biological chemistry 27 25480784
2019 The Role of Wnt and R-spondin in the Stomach During Health and Disease. Biomedicines 26 31248166
2018 R-spondin 2 promotes osteoblastic differentiation of immature human periodontal ligament cells through the Wnt/β-catenin signaling pathway. Journal of periodontal research 26 30284717
2013 Reconstitution of R-spondin:LGR4:ZNRF3 adult stem cell growth factor signaling complexes with recombinant proteins produced in Escherichia coli. Biochemistry 26 24050775
2017 An Eye Organoid Approach Identifies Six3 Suppression of R-spondin 2 as a Critical Step in Mouse Neuroretina Differentiation. Cell reports 25 29117559
2016 Novel Bispecific Domain Antibody to LRP6 Inhibits Wnt and R-spondin Ligand-Induced Wnt Signaling and Tumor Growth. Molecular cancer research : MCR 25 27401612
2013 R-Spondin 1 promotes vibration-induced bone formation in mouse models of osteoporosis. Journal of molecular medicine (Berlin, Germany) 25 23974989
2013 Syndecan-4 inhibits Wnt/β-catenin signaling through regulation of low-density-lipoprotein receptor-related protein (LRP6) and R-spondin 3. The international journal of biochemistry & cell biology 25 24275095
2013 LGR4 and its ligands, R-spondin 1 and R-spondin 3, regulate food intake in the hypothalamus of male rats. Endocrinology 25 24280058
2017 MicroRNA-493 suppresses hepatocellular carcinoma tumorigenesis through down-regulation of anthrax toxin receptor 1 (ANTXR1) and R-Spondin 2 (RSPO2). Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 24 28651234
2014 R-spondin 3 regulates dorsoventral and anteroposterior patterning by antagonizing Wnt/β-catenin signaling in zebrafish embryos. PloS one 24 24918770
2013 Secreted factor R-Spondin 2 is involved in refinement of patterning of the mammalian cochlea. Developmental dynamics : an official publication of the American Association of Anatomists 24 23192966
2013 Sexual dimorphism of AMH, DMRT1 and RSPO1 localization in the developing gonads of six anuran species. The International journal of developmental biology 24 24623081
2019 R-spondin 2 Drives Liver Tumor Development in a Yes-Associated Protein-Dependent Manner. Hepatology communications 23 31701073
2020 R-spondin signalling is essential for the maintenance and differentiation of mouse nephron progenitors. eLife 22 32324134
2016 R-spondin 2 promotes acetylcholine receptor clustering at the neuromuscular junction via Lgr5. Scientific reports 22 27328992
2023 R-spondin family biology and emerging linkages to cancer. Annals of medicine 21 36645115
2019 Mianserin suppresses R-spondin 2-induced activation of Wnt/β-catenin signaling in chondrocytes and prevents cartilage degradation in a rat model of osteoarthritis. Scientific reports 21 30808932
2018 The Matricellular Protein R-Spondin 2 Promotes Midbrain Dopaminergic Neurogenesis and Differentiation. Stem cell reports 21 30146491
2018 The role of R-spondin 1 through activating Wnt/β-catenin in the growth, survival and migration of ovarian cancer cells. Gene 21 30572097
2008 Mutations in the RSPO1 coding region are not the main cause of canine SRY-negative XX sex reversal in several breeds. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 21 18577875
2014 TALEN-mediated mutagenesis in zebrafish reveals a role for r-spondin 2 in fin ray and vertebral development. FEBS letters 20 25448983
2017 R-spondin 1 is required for specification of hematopoietic stem cells through Wnt16 and Vegfa signaling pathways. Development (Cambridge, England) 19 28087636
2017 R-spondin 2 promotes proliferation and migration via the Wnt/β-catenin pathway in human hepatocellular carcinoma. Oncology letters 19 28789406
2023 Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet-Induced Adiposity. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 36755192
2020 Rspo1/Rspo3-LGR4 signaling inhibits hepatic cholesterol synthesis through the AMPKα-SREBP2 pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18 32926477
2014 Engineering high-potency R-spondin adult stem cell growth factors. Molecular pharmacology 18 25504990
2007 Search for the sex-determining switch in monotremes: mapping WT1, SF1, LHX1, LHX2, FGF9, WNT4, RSPO1 and GATA4 in platypus. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 17 17717721
2018 Novel RSPO1 mutation causing 46,XX testicular disorder of sex development with palmoplantar keratoderma: A review of literature and expansion of clinical phenotype. American journal of medical genetics. Part A 16 29575617
2023 LGR4 and LGR5 form distinct homodimers that only LGR4 complexes with RNF43/ZNRF3 to provide high affinity binding of R-spondin ligands. Scientific reports 15 37402772
2022 Secondary bile acids mediate high-fat diet-induced upregulation of R-spondin 3 and intestinal epithelial proliferation. JCI insight 15 36099053
2019 Amphiregulin mediates the hormonal regulation on Rspondin-1 expression in the mammary gland. Developmental biology 15 31610144