Affinage

LGR5

Leucine-rich repeat-containing G-protein coupled receptor 5 · UniProt O75473

Length
907 aa
Mass
100.0 kDa
Annotated
2026-04-28
100 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LGR5 is a leucine-rich repeat-containing G-protein-coupled receptor that serves as a definitive marker and functional regulator of adult stem cells across numerous epithelial tissues, including intestine, stomach, liver, hair follicle, cochlea, ovary, tongue, and cartilage. LGR5 functions as a receptor for R-spondins (RSPO1–4), and upon RSPO binding it associates with the Frizzled/LRP6 Wnt receptor complex — distinct from LGR4, which instead sequesters the E3 ligases RNF43/ZNRF3 — to enhance LRP6 phosphorylation and potentiate canonical Wnt/β-catenin signaling, with RSPO driving active self-renewal and Wnt ligands maintaining RSPO receptor competency (PMID:21727895, PMID:33262293, PMID:28467820). LGR5+ stem cells undergo neutral-drift symmetric division, require Paneth cell- or alternative niche-derived signals (Wnt3, EGF, Notch ligands), and their persistent depletion compromises epithelial homeostasis, while in cancers LGR5+ cells function as tumor-propagating cancer stem cells essential for metastasis formation, yet LGR5− cells retain plasticity to regenerate LGR5+ populations (PMID:20887898, PMID:21113151, PMID:33503423, PMID:28355176, PMID:28358093). Beyond canonical Wnt potentiation, LGR5 engages TGFβ receptor complexes to enhance TGFβ signaling, promotes cytoneme-like membrane protrusions, undergoes constitutive ligand-independent internalization to lysosomes, and in cartilage establishes a Wnt-inhibitory niche that maintains chondroprogenitor identity (PMID:28939678, PMID:25653388, PMID:27207778, PMID:37683603).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2007 High

    The identity of the long-sought intestinal stem cell was resolved when lineage tracing showed that LGR5+ crypt base columnar cells are self-renewing, multipotent stem cells generating all epithelial lineages, establishing LGR5 as the first definitive adult intestinal stem cell marker.

    Evidence Knock-in Lgr5-EGFP-IRES-creERT2 allele with Rosa26-lacZ lineage tracing in mouse intestine

    PMID:17934449

    Open questions at the time
    • Mechanism by which LGR5 itself contributes to stemness versus serving as a passive marker was unknown
    • Whether LGR5 marks stem cells in other organs was untested
  2. 2009 High

    The question of whether LGR5+ cells possess intrinsic stem cell capacity independent of their mesenchymal niche was answered when single sorted LGR5+ cells generated self-organizing crypt-villus organoids, while knockout studies revealed LGR5 negatively regulates Wnt signaling during development.

    Evidence Single-cell 3D organoid culture (PMID:19329995); LGR5-null mice showing precocious Paneth cell differentiation and upregulated Wnt targets (PMID:19394326)

    PMID:19329995 PMID:19394326

    Open questions at the time
    • The ligand for LGR5 remained unknown
    • How LGR5 negatively regulates Wnt while marking Wnt-dependent stem cells was paradoxical
  3. 2010 High

    The stem cell division mode and niche architecture were defined: LGR5+ ISCs divide symmetrically following neutral drift dynamics, and Paneth cells were identified as the essential niche providing EGF, Wnt3, and Notch ligands to maintain LGR5+ stem cells.

    Evidence Multicolor clonal fate mapping quantifying neutral drift (PMID:20887898); Paneth cell co-culture/genetic ablation showing niche dependency (PMID:21113151); gastric Lgr5+ lineage tracing extending the stem cell paradigm to stomach (PMID:20085740)

    PMID:20085740 PMID:20887898 PMID:21113151

    Open questions at the time
    • Whether alternative niche cells could substitute for Paneth cells was unknown
    • The molecular receptor-ligand mechanism connecting LGR5 to Wnt pathway components was unresolved
  4. 2011 High

    The central ligand-receptor mechanism was established: R-spondins (RSPO1-4) were identified as LGR5 ligands that bind via Furin domains, and LGR5/LGR4 were shown to associate with the Frizzled/LRP Wnt receptor complex to potentiate canonical Wnt/β-catenin signaling, with double knockout phenocopying Wnt pathway loss.

    Evidence Mass spectrometry interactome, conditional Lgr4/5 double knockout in gut, HEK293 signaling assays (PMID:21727895); domain binding and endocytosis pathway dissection in mammalian cells and Xenopus (PMID:21909076)

    PMID:21727895 PMID:21909076

    Open questions at the time
    • Whether LGR4 and LGR5 engage the same downstream effectors or have distinct mechanisms was unclear
    • The relationship between RSPO-LGR signaling and the RNF43/ZNRF3 E3 ligase axis was not yet defined
  5. 2012 High

    LGR5's stem cell-marking function was extended beyond gut and stomach to cochlear hair cell progenitors, establishing it as a pan-tissue adult stem cell marker.

    Evidence Sorting of LGR5+ cochlear supporting cells, Wnt-responsive neurosphere formation, and lineage tracing showing hair cell differentiation

    PMID:22787049

    Open questions at the time
    • Functional requirement of LGR5 signaling (versus marker status) in non-intestinal tissues was not demonstrated
    • Whether LGR5 marks stem cells in all Wnt-dependent tissues remained open
  6. 2013 High

    LGR5+ cells were shown to function as damage-induced bipotent liver progenitors capable of generating hepatocytes and bile ducts, with RSPO1 as the critical niche ligand, extending the LGR5 stem cell paradigm to solid organ regeneration.

    Evidence Lineage tracing of injury-induced Lgr5+ liver cells, single-cell organoid expansion, functional hepatocyte transplantation into Fah−/− mice

    PMID:23354049

    Open questions at the time
    • Whether LGR5+ liver cells exist during homeostasis or only emerge after injury was debated
    • The upstream signals inducing LGR5 expression in damaged liver were unknown
  7. 2014 High

    The downstream effector mechanism was clarified: LGR5/RSPO complexes neutralize the transmembrane E3 ligases RNF43/ZNRF3, which normally remove Wnt receptors from the cell surface, thereby closing a negative feedback loop to sustain Wnt signaling; complementary knockout studies showed LGR4 is the dominant embryonic paralog.

    Evidence Mechanistic synthesis of genetic and biochemical data (PMID:24532711); conditional Lgr4/5 knockout epistasis in embryonic tissues (PMID:24680895); LGR5+ stem cells further validated in ovary (PMID:24997521) and taste buds (PMID:25368147)

    PMID:24532711 PMID:24680895 PMID:24997521 PMID:25368147

    Open questions at the time
    • Whether LGR5 itself directly binds RNF43/ZNRF3 or acts through LGR4 was unresolved
    • Structural basis of the LGR5-RSPO-E3 ligase interaction was lacking
  8. 2015 High

    Multiple niche-regulatory pathways converging on LGR5+ stem cells were defined: Yap reprograms LGR5+ ISCs after injury, Notch directly regulates LGR5+ gastric stem cell proliferation via mTORC1, and LGR5 itself promotes cytoneme-like protrusions and can activate noncanonical signaling (AP-1/Jun) in adrenal cells.

    Evidence Conditional Yap deletion and irradiation model (PMID:26503053); in vivo Notch manipulation in gastric Lgr5+ cells (PMID:26271103); live imaging of LGR5-induced cytonemes (PMID:25653388); LGR5 overexpression in adrenal cells (PMID:25915569)

    PMID:25653388 PMID:25915569 PMID:26271103 PMID:26503053

    Open questions at the time
    • Whether LGR5's cytoneme-inducing activity is relevant in vivo was untested
    • The physiological significance of LGR5-mediated noncanonical signaling relative to canonical Wnt potentiation was unclear
  9. 2017 High

    The non-equivalent cooperative roles of Wnt and RSPO were established — Wnt maintains RSPO receptor competency while RSPO drives self-renewal — and LGR5+ cancer stem cells were shown to be essential for metastasis but dispensable for primary tumor maintenance, with LGR5− cells retaining plasticity to regenerate LGR5+ cells.

    Evidence Non-lipidated Wnt analogue distinguishing Wnt versus RSPO functions (PMID:28467820); LGR5+ CSC ablation in human organoids showing plasticity (PMID:28355176); mouse CRC model showing LGR5+ cells required for metastasis (PMID:28358093); RSPO-LGR5 cross-talk with TGFβ receptors (PMID:28939678); macrophage TNF activating Lgr5+ hair follicle SCs via AKT/β-catenin (PMID:28345588)

    PMID:28345588 PMID:28355176 PMID:28358093 PMID:28467820 PMID:28939678

    Open questions at the time
    • The signals driving LGR5− to LGR5+ plasticity during metastatic outgrowth were undefined
    • Whether the LGR5-TGFβ receptor interaction occurs in normal stem cells or only in cancer was unknown
  10. 2019 High

    Niche flexibility was demonstrated — enteroendocrine and tuft cells substitute for Paneth cells as Notch signal sources — and the RSPO3-LGR5 axis was shown to have a bifunctional role in gastric antimicrobial defense against H. pylori alongside mucosal regeneration; NOD2-dependent mitophagy was identified as a cytoprotective mechanism for LGR5+ ISCs.

    Evidence Paneth cell ablation with single-cell sequencing revealing alternative Notch sources (PMID:31843916); Rspo3 knockout/overexpression and Lgr5+ cell depletion affecting H. pylori colonization (PMID:31235935); NOD2/ATG16L1 knockout organoids under oxidative stress (PMID:31919280)

    PMID:31235935 PMID:31843916 PMID:31919280

    Open questions at the time
    • The full spectrum of niche-derived signals sufficient to maintain LGR5+ ISCs in the complete absence of Paneth cells was not defined
    • Whether the antimicrobial function of RSPO3-LGR5 extends to other pathogens was untested
  11. 2020 High

    The mechanistic distinction between LGR4 and LGR5 was resolved: LGR4 constitutively binds RNF43/ZNRF3 via its transmembrane domain whereas LGR5 does not interact with either E3 ligase but instead associates with FZD/LRP6 to enhance LRP6 phosphorylation, and both receptors exist as cell-surface dimers; concurrently, LGR5− disseminated cancer cells were shown to seed metastases with LGR5+ cells re-emerging for outgrowth.

    Evidence Co-IP, proximity ligation, TR-FRET, and domain-swapping experiments (PMID:33262293); mouse CRC model and xenograft lineage tracing of LGR5 plasticity during metastasis (PMID:32169167)

    PMID:32169167 PMID:33262293

    Open questions at the time
    • Structural basis distinguishing LGR5's FZD/LRP6 interaction from LGR4's E3 ligase interaction was lacking
    • Whether LGR5 dimerization is required for signaling was untested
  12. 2021 High

    The obligatory requirement for LGR5+ stem cells was demonstrated in both normal homeostasis (persistent depletion compromises intestinal epithelial integrity) and cancer (LGR5+ cells are required for gastric cancer initiation, maintenance, and metastasis).

    Evidence Lgr5-2A-DTR near-complete ablation model showing homeostatic failure (PMID:33503423); Lgr5+ cell ablation in orthotopic gastric cancer organoid transplants (PMID:34857912)

    PMID:33503423 PMID:34857912

    Open questions at the time
    • The extent to which reserve/quiescent stem cell populations can compensate for LGR5+ cell loss long-term remained debated
    • Whether LGR5 itself is required or LGR5 expression merely marks the required population was unresolved
  13. 2022 High

    Quiescent LGR5+p27+ cells were identified in the human colon with augmented clonogenic capacity, regulated by TGFβ signaling; IL-17A signaling through IL-17RA in LGR5+ ISCs was shown to drive secretory cell differentiation via ATOH1 induction, expanding the known regulatory inputs to LGR5+ stem cells.

    Evidence Genome-engineered human organoid reporters with scRNA-seq and xenotransplantation (PMID:35963362); conditional IL-17RA and ATOH1 deletion in Lgr5+ cells (PMID:35081371)

    PMID:35081371 PMID:35963362

    Open questions at the time
    • The molecular switch between quiescent and active LGR5+ stem cell states was not fully defined
    • How IL-17A signaling is integrated with RSPO-Wnt inputs at the LGR5+ cell level was unknown
  14. 2023 High

    LGR5's function was extended beyond a stem cell marker to an active niche regulator: in cartilage, LGR5-expressing secretory cells form a Wnt-inhibitory niche that maintains chondroprogenitor identity, and LGR5 ablation produces phenotypically unstable chondrocytes.

    Evidence Genetic lineage tracing and Lgr5 ablation in multiple species with single-cell RNA sequencing

    PMID:37683603

    Open questions at the time
    • The molecular mechanism by which LGR5+ cells create a Wnt-inhibitory environment in cartilage was not characterized
    • Whether LGR5 acts as a Wnt sink or through RSPO sequestration in cartilage was unknown
  15. 2024 High

    Biophysical properties distinguishing LGR5+ cancer stem cells were defined: LGR5+ CRC cells are stiffer, adhere better, and form larger transendothelial gaps, explained by downregulation of ERM membrane-cortex linkers, linking LGR5+ identity to mechanotransduction and metastatic behavior.

    Evidence Atomic force microscopy, patient-derived organoids, scRNA-seq validation of ERM downregulation

    PMID:38637494

    Open questions at the time
    • Whether ERM downregulation is a cause or consequence of LGR5+ identity was not established
    • Functional rescue of ERM in LGR5+ cells to test metastatic competence was not performed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of LGR5's selective interaction with FZD/LRP6 versus LGR4's interaction with RNF43/ZNRF3; the molecular mechanisms governing LGR5− to LGR5+ plasticity in cancer; whether LGR5 has signaling functions independent of Wnt potentiation in vivo; and what determines whether LGR5+ cells serve as stem cells versus niche-organizing cells across tissues.
  • No high-resolution structure of LGR5 in complex with FZD/LRP6 or RSPO
  • Epigenetic or transcriptional programs governing LGR5 reactivation in differentiated cancer cells are uncharacterized
  • Whether LGR5-induced cytonemes play a physiological signaling role in stem cell niches is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 2 GO:0005764 lysosome 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 3 R-HSA-1640170 Cell Cycle 2
Partners
ARRB2FZDLGR4LRP6MYO10RSPO1RSPO3TGFBR2
Complex memberships
Frizzled/LRP6 Wnt signalosome

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 LGR5 (also known as Gpr49) marks cycling columnar cells at the crypt base of small intestine and colon, and lineage-tracing experiments demonstrated that LGR5+ crypt base columnar cells are self-renewing, multipotent stem cells that generate all epithelial lineages over a 60-day period. Knock-in allele generation, in vivo lineage tracing with Rosa26-lacZ reporter Nature High 17934449
2009 Single sorted LGR5+ stem cells can initiate self-organizing crypt-villus organoids in vitro without a mesenchymal niche, demonstrating LGR5+ cells have full stem cell capacity for self-renewal and multilineage differentiation. Single-cell sorting, 3D organoid culture, lineage tracing Nature High 19329995
2009 LGR5 deficiency in mice leads to precocious Paneth cell differentiation and upregulation of Wnt target genes in the developing intestine, identifying LGR5 as a negative regulator of the Wnt pathway in the developing intestine, with evidence of an autoregulatory negative feedback loop. LGR5 null/LacZ knock-in mice, quantitative RT-PCR, transcriptional profiling Developmental biology High 19394326
2010 Lgr5+ intestinal stem cells undergo symmetric divisions and follow neutral drift dynamics, with most divisions producing two equivalent daughter cells that stochastically adopt stem or transit-amplifying fates, driving crypt drift toward clonality. Multicolor Cre-reporter fate mapping (individual stem cell tracing), quantitative clonal analysis Cell High 20887898
2010 Paneth cells physically associate with Lgr5+ stem cells and provide essential niche signals (EGF, TGF-α, Wnt3, Notch ligand Dll4); co-culturing sorted stem cells with Paneth cells markedly improves organoid formation, and genetic removal of Paneth cells in vivo causes concomitant loss of Lgr5+ stem cells. Co-culture of sorted stem and Paneth cells, organoid formation assay, genetic Paneth cell ablation in vivo, immunofluorescence Nature High 21113151
2010 LGR5 marks self-renewing, multipotent stem cells at the base of gastric pyloric glands; lineage tracing in vivo shows these cells are responsible for long-term renewal of the gastric epithelium, and single Lgr5+ cells generate long-lived gastric organoids in vitro. In vivo lineage tracing, single-cell organoid culture Cell stem cell High 20085740
2011 LGR4 and LGR5 associate with the Frizzled/LRP Wnt receptor complex (by mass spectrometry) and serve as receptors for R-spondins (RSPO1-4); RSPO binding to LGR4/5 enhances canonical Wnt signaling, and removal of LGR4 abrogates RSPO-mediated signal enhancement. Conditional deletion of both Lgr4 and Lgr5 in mouse gut impairs Wnt target gene expression and causes rapid crypt demise, phenocopying Wnt pathway inhibition. Mass spectrometry interactome, conditional double knockout, HEK293 signaling assays, organoid culture rescue experiments Nature High 21727895
2011 LGR4 and LGR5 bind R-spondins via their Furin domains, and gain- and loss-of-function experiments show that LGR4 and LGR5 promote R-spondin-mediated Wnt/β-catenin and Wnt/PCP signaling. R-spondin-triggered β-catenin signaling requires Clathrin, while Wnt3a-mediated β-catenin signaling requires Caveolin-mediated endocytosis. Gain- and loss-of-function experiments in mammalian cells and Xenopus embryos, domain binding assays EMBO reports High 21909076
2012 LGR5 marks Wnt-responsive cochlear supporting cells that serve as hair cell progenitors; sorted LGR5+ cells show enhanced neurosphere formation in response to Wnt and convert to hair cells at >10-fold higher rate than unsorted cells; lineage tracing confirmed LGR5+ cells form neurospheres and differentiate to hair cells. Flow cytometry sorting, neurosphere culture, Wnt stimulation assay, lineage tracing The Journal of neuroscience High 22787049
2013 Damage-induced Lgr5+ cells appear near bile ducts in mouse liver upon injury and generate hepatocytes and bile ducts in vivo by lineage tracing; single Lgr5+ cells from damaged liver expand clonally as organoids and generate functional hepatocytes upon transplantation into Fah-/- mice. RSPO1 is identified as a crucial Wnt agonist/LGR5 ligand for this culture system. Lgr5-IRES-creERT2 lineage tracing, single-cell clonal organoid expansion, transplantation into Fah-/- mice Nature High 23354049
2014 The LGR5/R-spondin complex acts by neutralizing RNF43 and ZNRF3, two transmembrane E3 ligases that remove Wnt receptors from the stem cell surface; RNF43/ZNRF3 are themselves Wnt target genes forming a negative feedback loop, and LGR5/R-spondin binding disrupts this feedback to enhance Wnt signaling. Review synthesizing genetic and biochemical evidence from multiple studies Genes & development High 24532711
2014 Single Lgr5+ or Lgr6+ taste cells can generate continuously expanding 3D organoids containing functional mature taste receptor cells, and lineage tracing showed Lgr6+ cells give rise to taste bud cells in anterior and posterior tongue; Lgr5 and Lgr6 may mark the same subset of taste stem/progenitor cells. Single-cell organoid culture, calcium imaging of tastant responses, genetic lineage tracing Proceedings of the National Academy of Sciences of the United States of America High 25368147
2014 Lgr5 expression in mouse ovary is restricted to proliferative regions of the ovarian surface epithelium (OSE) and mesovarian-fimbria junctional epithelia; in vivo lineage tracing identifies Lgr5+ populations as stem/progenitor cells contributing to OSE development and ovulatory regenerative repair. Reporter mice, single-molecule FISH, in vivo lineage tracing Nature cell biology High 24997521
2014 Conditional deletion of Lgr4 (but not Lgr5 alone) in embryonic mice leads to complete loss of Lgr5+/Olfm4+ intestinal stem cells, compromised Wnt signaling, and impaired proliferation and differentiation of gut epithelium, as well as reduced hair follicle numbers and dilated kidney tubules; Lgr4 and Lgr5 have complementary functions in embryonic development with Lgr4 dominant. Conditional knockout mice (Lgr4KO, Lgr5KO, Lgr4/5dKO), histology, immunofluorescence Developmental biology High 24680895
2014 GATA6 transcription factor directly enhances LGR5 expression in colorectal cancer cells; miR-363 targets GATA6 and its downregulation leads to upregulation of GATA6 and consequently LGR5, promoting colorectal tumourigenicity. Transcription factor binding assay, miRNA functional studies, loss-of-function in colorectal cancer cells Nature communications Medium 24452072
2015 Yap transiently reprograms Lgr5+ intestinal stem cells after irradiation injury by suppressing Wnt signaling and excessive Paneth cell differentiation, promoting cell survival, and inducing a regenerative program including EGF pathway activation; Yap inactivation abolishes adenomas in Apc(Min) mice and blocks Lgr5+ ISC-driven tumorigenesis. Conditional Yap deletion in mice, organoid culture with/without epiregulin rescue, Apc(Min) genetic epistasis, irradiation model Nature High 26503053
2015 LGR5 in the human adrenal zona glomerulosa activates the noncanonical AP-1/Jun pathway (more than canonical Wnt) and inhibits aldosterone production; overexpression of LGR5 or stimulation with its ligand R-spondin-3 suppresses aldosterone synthesis and reduces cell proliferation while increasing apoptosis in human adrenal cells. LGR5 transfection and R-spondin-3 stimulation of human adrenal cells, TOP-Flash and AP-1 reporter assays, cell kinetics measurement The Journal of clinical endocrinology and metabolism Medium 25915569
2015 Notch signaling is intrinsic to the gastric epithelium and directly regulates LGR5+ antral stem cell homeostasis: pathway inhibition reduced stem and progenitor cell proliferation and induced differentiation, while constitutive Notch activation in LGR5+ stem cells induced gland fission via mTORC1 signaling and competitive advantage over unmanipulated stem cells. In vivo Notch manipulation, gastric organoid culture, lineage tracing with multicolor reporter, mTORC1 inhibitor rescue The EMBO journal High 26271103
2015 LGR5 promotes long actin-rich cytoneme-like membrane protrusions (>80 µm) through stabilization of nascent filopodia; LGR5-induced cytonemes act as conduits for cell signaling, with myosin X (Myo10) and β-arrestin-2 (Arrb2) transiting into these protrusions. Live cell imaging, fluorescently tagged protein constructs, functional protrusion measurements Journal of cell science Medium 25653388
2015 LGR5 knockdown in neuroblastoma cell lines induces Wnt-independent apoptosis accompanied by greatly diminished phosphorylation of MEK1/2 and ERK1/2, increased BimEL, decreased Akt signaling via a Rictor-dependent/PDK1-independent mechanism, and G1 cell-cycle arrest with increased p27 and decreased phospho-Rb. siRNA knockdown, western blotting for signaling intermediates, cell cycle analysis, apoptosis assays Oncotarget Medium 26517508
2015 SOX9 transcription factor directly enhances LGR5 expression in glioblastoma cells; knockdown of SOX9 suppresses LGR5 expression and reduces proliferation and tumorigenicity of glioblastoma cells, establishing a SOX9-LGR5 transcriptional axis. siRNA knockdown, reporter assays, in vitro proliferation and in vivo xenograft assays Biochemical and biophysical research communications Medium 25770425
2017 Wnt and RSPO ligands have qualitatively distinct, non-interchangeable roles: Wnt ligands confer a basal competency by maintaining RSPO receptor (LGR5) expression, while RSPO ligands actively drive and specify the extent of Lgr5+ ISC self-renewal. The default fate of Lgr5+ ISCs is differentiation unless both RSPO and Wnt ligands are present. Non-lipidated Wnt analogue, RSPO gain-of-function, genetic and pharmacological perturbations of ISC niche, organoid culture Nature High 28467820
2017 In adult lung, LGR5 marks mesenchymal cells (not epithelial stem cells) in alveolar compartments; Lgr5+ mesenchymal cells promote alveolar differentiation of epithelial progenitors through Wnt activation, while distinct Lgr6+ smooth muscle cells promote airway differentiation via Wnt-Fgf10 cooperation. Genetic ablation of Lgr6+ cells impairs airway injury repair. Genetic lineage tracing, single-cell RNA sequencing, organoid co-culture, genetic ablation Cell High 28886383
2017 R-spondin-1/LGR5 directly activates TGFβ signaling cooperatively with TGFβ type II receptor in colon cancer cells; upon RSPO1 stimulation, LGR5 forms complexes with TGFβ receptors, enhancing TGFβ-mediated growth inhibition and stress-induced apoptosis; LGR5 knockdown reduces TGFβ signaling and increases metastasis in vivo. Co-immunoprecipitation of LGR5-TGFβ receptor complexes, LGR5 knockdown, orthotopic xenograft model Cancer research Medium 28939678
2017 Lgr5+ cancer stem cells (CSCs) identified by tamoxifen-inducible Cre knock-in in human colorectal cancer organoids show self-renewal and differentiation capacity by lineage tracing; selective ablation of LGR5+ CSCs causes tumor regression but leads to regrowth driven by re-emerging LGR5+ CSCs from LGR5- differentiated cells (KRT20+) demonstrating plasticity. LGR5-iCaspase9 knock-in organoids, LGR5 tamoxifen-inducible Cre lineage tracing, KRT20-ERCreER knock-in reporter Nature High 28355176
2017 Selective ablation of Lgr5+ CSCs in mouse colorectal tumors restricts primary tumor growth but does not cause regression; Lgr5+ CSCs are critical for formation and maintenance of liver metastases from colorectal cancers, demonstrating distinct CSC dependencies for primary vs. metastatic tumor growth. Lgr5+ selective cell ablation in engineered mouse colorectal cancer model, metastasis assay Nature High 28358093
2017 Macrophage-derived TNF induces AKT/β-catenin-dependent Lgr5+ hair follicle stem cell activation and hair follicle regeneration; TNF-induced β-catenin accumulation is dependent on AKT but not Wnt signaling; Pten loss in Lgr5+ HF stem cells results in hair follicle telogen-anagen transition independent of injury. TNF knockout and overexpression mouse models, PI3K/AKT inhibition, Pten conditional deletion in Lgr5+ cells, in vitro AKT signaling assays Nature communications High 28345588
2019 R-spondin-3 (Rspo3) induces differentiation of basal Lgr5+ gastric cells into secretory cells that express and secrete antimicrobial factors (e.g., intelectin-1); depletion of Lgr5+ cells or knockout of Rspo3 in myofibroblasts leads to hypercolonization of gastric glands by H. pylori, while Rspo3 overexpression clears H. pylori—establishing a bifunctional Rspo3-Lgr5 axis regulating both antimicrobial defense and mucosal regeneration. Lgr5+ cell depletion, Rspo3 myofibroblast-specific knockout, Rspo3 systemic administration, organoid culture Nature cell biology High 31235935
2019 Lgr5+ pericentral hepatocytes in adult mouse liver have a long lifespan and mainly self-renew during postnatal liver development, homeostasis, and partial hepatectomy-induced regeneration; they are the major cellular origin of diethylnitrosamine-induced hepatocellular carcinoma and are highly susceptible to neoplastic transformation via Erbb pathway activation. BAC-transgenic mouse model, genetic lineage tracing, partial hepatectomy, DEN-induced HCC model Proceedings of the National Academy of Sciences of the United States of America High 31488716
2020 Most disseminated colorectal cancer cells in circulation are LGR5- and seed distant metastases, after which LGR5+ CSCs re-emerge; plasticity from LGR5- to LGR5+ occurs independently of stemness-inducing microenvironmental factors and is indispensable for outgrowth (but not establishment) of metastases. Mouse colorectal cancer model, human tumor xenografts, in vivo lineage tracing, flow cytometric sorting Cell stem cell High 32169167
2020 Full-length LGR4 (but not LGR5) forms a tight complex with ZNRF3 and RNF43 E3 ligases even without RSPO; LGR5 does not interact with either E3 ligase with or without RSPO. The seven-transmembrane domain of LGR4 confers E3 ligase interaction. LGR5 instead interacts with FZD and LRP6 of the Wnt signalosome to enhance LRP6 phosphorylation and potentiate Wnt-β-catenin signaling. LGR4 and LGR5 exist as dimers on the cell surface. Co-immunoprecipitation, proximity ligation assay, competition binding assay, time-resolved FRET, domain-swapping experiments Science signaling High 33262293
2021 Tumor-resident Lgr5+ stem-like cells are critical to initiation and maintenance of gastric cancer tumor burden and obligatory for establishment of metastases, as demonstrated by in vivo ablation of Lgr5+ cells in orthotopic cancer organoid transplantation models. Conditional Lgr5 ablation in orthotopic cancer organoid transplantation model, in vivo tumor and metastasis assessment Nature cell biology High 34857912
2021 Persistent depletion of Lgr5+ ISCs using a Lgr5-2A-DTR model (with near-complete ablation efficiency) compromises small intestinal epithelial integrity and reduces epithelial turnover in vivo, establishing that intestinal homeostasis requires a constant pool of Lgr5+ ISCs. Diphtheria toxin receptor knock-in (Lgr5-2A-DTR), in vivo Lgr5+ cell depletion, organoid culture with DT treatment Cell reports High 33503423
2022 IL-17A signaling through IL-17RA in Lgr5+ intestinal epithelial stem cells induces the transcription factor ATOH1, promoting secretory epithelial cell differentiation; Paneth, tuft, goblet, and enteroendocrine cell numbers depend on this IL-17A/ATOH1 axis in Lgr5+ ISCs, and IL-17RA signaling is required to regenerate secretory cells following injury. Multiple conditional deletion mouse models (IL-17RA in Lgr5+ cells and ATOH1+ cells), human intestinal organoid stimulation, injury-regeneration assays Immunity High 35081371
2022 Quiescent LGR5+p27+ cells exist in the human colon, validated by single-cell RNA sequencing and p27-mVenus reporter; TGF-β signaling regulates the quiescent state of LGR5+ cells; these slow-cycling cells have augmented clonogenic capacity after injury, and their niche occupancy prevents neighboring differentiated KRT20+ cells from de-differentiating. Single-cell RNA sequencing, genome-engineered human colon organoids (LGR5-tdTomato, LGR5-iCaspase9, p27-mVenus reporter), orthotopic xenotransplantation, EdU pulse-chase, LGR5 ablation experiments Gastroenterology High 35963362
2023 Lgr5-expressing secretory cells form a Wnt inhibitory niche in cartilage that instructs Wnt-inactive chondroprogenitors and maintains chondrocyte identity; Lgr5 ablation during joint development, aging, or osteoarthritis depletes Wnt-inactive chondroprogenitors and produces phenotypically unstable chondrocytes with osteoblast-like properties. Genetic lineage tracing, Lgr5 ablation in multiple species, single-cell RNA sequencing, in vivo cartilage functional assays Cell stem cell High 37683603
2019 NOD2 activation by muramyl dipeptide (MDP) protects LGR5+ intestinal stem cells from oxidative stress-induced death via mitophagy induction, dependent on coordinated activation of NOD2 and ATG16L1 through an NF-κB-independent pathway; ATG16L1 KO and NOD2 KO organoids do not benefit from MDP-induced cytoprotection. Murine intestinal organoids, irradiation stress model, ATG16L1 and NOD2 knockout organoids, ROS and mitophagy assays, in vivo confirmation Proceedings of the National Academy of Sciences of the United States of America High 31919280
2016 LGR5 undergoes rapid, constitutive internalization to lysosomes independent of ligand; LGR5-targeted antibody-drug conjugates (ADC) bind LGR5, internalize to lysosomes, and induce cytotoxicity selectively in LGR5-expressing gastrointestinal cancer cells in vitro and eradicate tumors in xenograft models. Receptor internalization assay, cell-based cytotoxicity, xenograft tumor model Molecular cancer therapeutics Medium 27207778
2024 LGR5+ colorectal cancer stem cells are stiffer, adhere better to ECM, move slower, display higher nuclear YAP, and form larger transendothelial gaps compared to LGR5- cells; these differences are largely explained by downregulation of ERM (Ezrin/Radixin/Moesin) membrane-to-cortex attachment proteins in LGR5+ cells, a signature confirmed in patient scRNA-seq data. Patient-derived organoids, atomic force microscopy, single-cell RNA sequencing, ERM protein analysis Nature communications High 38637494
2019 Enteroendocrine and tuft cells can substitute for Paneth cells as an alternative source of Notch signals to maintain Lgr5+ intestinal stem cells when Paneth cells are ablated, demonstrating niche flexibility in maintaining Lgr5+ ISC maintenance. Diphtheria toxin receptor-mediated Paneth cell ablation in vivo, flow cytometry, single-cell sequencing, histological analysis Proceedings of the National Academy of Sciences of the United States of America High 31843916

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 5553 19329995
2007 Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 4557 17934449
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