Affinage

IHH

Indian hedgehog protein · UniProt Q14623

Length
411 aa
Mass
45.3 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IHH is a secreted hedgehog-family morphogen that serves as a master coordinator of endochondral bone formation, coupling chondrocyte proliferation, hypertrophic differentiation, and osteoblast specification through distinct paracrine signaling circuits. Produced by prehypertrophic chondrocytes, IHH signals through the PTCH1–SMO–GLI axis at the primary cilium to restrain chondrocyte hypertrophy via a PTHrP-dependent negative-feedback loop—whose range is tuned by heparan sulfate proteoglycans—while also promoting chondrocyte proliferation and inducing osteoblast differentiation in perichondrial progenitors through Gli2-mediated transcriptional activation of Runx2 (PMID:11517919, PMID:14973297, PMID:16284117, PMID:17442891, PMID:15177029). Gli3 repressor is the principal antagonist of IHH-dependent chondrocyte responses, with its levels controlled by SPOP/Cullin-3-mediated ubiquitination, and EVC at the ciliary base is required for pathway output downstream of SMO (PMID:16141219, PMID:27930311, PMID:17660199). IHH transcription is activated by Atf4, Runx2/Cbfβ, and Wnt9a/β-catenin binding to its promoter, repressed by δ-EF1 (via intron 1) and Hand1, and modulated by at least nine additive enhancers whose copy-number alterations cause craniosynostosis or brachydactyly (PMID:19906842, PMID:24821091, PMID:16818445, PMID:19948490, PMID:28846100, PMID:19252479). Beyond the skeleton, IHH functions in uterine receptivity under SOX17/progesterone-receptor control, ovarian theca cell steroidogenesis, and dose-dependent regulation of thymic T-cell development (PMID:30356064, PMID:29788357, PMID:19109233).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2001 High

    Establishing the essential signal transducer: genetic epistasis showed SMO is the obligate transducer of all hedgehog signals including IHH, resolving whether IHH uses the same receptor-effector axis as SHH.

    Evidence Compound Smo/Shh/Ihh knockout mouse embryos with identical phenotypes

    PMID:11440720 PMID:11517919

    Open questions at the time
    • Downstream transcriptional effectors (Gli proteins) not yet dissected for IHH specifically
    • Cell-type-specific signal requirements not addressed
  2. 2001 High

    Separating BMP and IHH inputs: BMP signaling acts in parallel to IHH rather than as its downstream mediator for PTHrP induction or proliferation control, clarifying the growth plate signaling hierarchy.

    Evidence Mouse limb explant organ culture with BMP2, Noggin, cyclopamine; Ihh-overexpressing transgenic mice

    PMID:11714677

    Open questions at the time
    • How BMP modulates Ihh expression levels mechanistically undefined
    • FGF pathway intersection not yet mapped
  3. 2002 High

    Mapping FGF–IHH antagonism: activating FGFR3 mutations reduce IHH/PTHrP signaling and accelerate hypertrophy, positioning FGF as an upstream negative regulator of the IHH–PTHrP axis in disease-relevant contexts.

    Evidence Limb explant culture with FGF ligands, cyclopamine; mouse achondroplasia model

    PMID:12361605

    Open questions at the time
    • Whether FGF directly represses Ihh transcription or acts post-translationally
    • In vivo epistasis between FGFR3 and Ihh not performed
  4. 2004 High

    Demonstrating IHH's osteoblast-inducing role: conditional Smo deletion in perichondrium showed IHH signaling is directly required for osteoblast specification, and without it, progenitors default to chondrocyte fate.

    Evidence Cre-LoxP conditional Smo knockout in perichondrial cells; chimeric embryo analysis

    PMID:14973297

    Open questions at the time
    • Transcription factor mediating the osteoblast switch not yet identified
    • Whether IHH acts as a mitogen or differentiation signal on perichondrium unclear
  5. 2004 High

    Defining morphogen range control: heparan sulfate proteoglycans (via Ext1) concentration-dependently restrict IHH movement, revealing how extracellular matrix tunes the IHH signaling gradient that regulates PTHrP expression at a distance.

    Evidence Hypomorphic Ext1 mutant mice with paradoxically increased IHH signaling range

    PMID:15177029

    Open questions at the time
    • Exact biochemical mode of HS–IHH interaction (sequestration vs. co-receptor) unresolved
    • Other extracellular modulators not surveyed
  6. 2005 High

    Identifying Gli3 repressor as the principal IHH antagonist: double-mutant analysis showed Gli3 removal restores chondrocyte proliferation and PTHrP expression in Ihh-null embryos, establishing that IHH acts largely by relieving Gli3-mediated repression, though osteoblast rescue was incomplete.

    Evidence Ihh−/−;Gli3−/− compound mutant mice with molecular and histological phenotyping

    PMID:16141219 PMID:16284117

    Open questions at the time
    • Identity of the vasculature-derived signal that cooperates with IHH for osteogenesis unknown
    • Relative contributions of Gli activators vs. Gli3 repressor in specific cell types not quantified
  7. 2006 High

    Placing Wnt/β-catenin upstream of IHH: Wnt9a regulates Ihh transcription via β-catenin/Lef1 binding directly to the Ihh promoter, establishing a transcriptional hierarchy linking canonical Wnt signaling to hedgehog output in chondrocytes.

    Evidence Wnt9a knockout mice; in vivo ChIP of β-catenin/Lef1 on Ihh promoter

    PMID:16818445

    Open questions at the time
    • Whether other Wnt ligands contribute redundantly
    • Quantitative contribution of Wnt-driven Ihh vs. other transcriptional inputs
  8. 2007 High

    Resolving the Gli2–Runx2 effector axis for osteoblast induction: IHH promotes osteoblast differentiation through Gli2, which upregulates Runx2 and physically interacts with it; Gli2 acts exclusively as a transcriptional activator in this context.

    Evidence Co-immunoprecipitation of Gli2–Runx2; dominant-negative Gli2; Runx2-deficient cell rescue; Gli2/Gli3 compound mutant mice

    PMID:17442891 PMID:20503377

    Open questions at the time
    • Genomic targets co-bound by Gli2–Runx2 complex not mapped
    • Whether Foxc1–Gli2 interaction identified later is the same complex
  9. 2007 High

    Proving direct IHH signaling to chondrocytes: tamoxifen-inducible Smo deletion specifically in chondrocytes demonstrated IHH signals directly to chondrocytes (not just via perichondrium) to control PTHrP expression and cell morphology.

    Evidence Col2-CreERT2 Smo conditional knockout in chondrocytes with molecular analysis

    PMID:17560974

    Open questions at the time
    • Whether direct and indirect (perichondrial relay) signals contribute equally in vivo
  10. 2007 High

    Linking ciliary machinery to IHH: EVC localizes to the primary cilium base and is required for transcriptional output of IHH targets downstream of SMO, without affecting Gli3 processing.

    Evidence Evc knockout mice; immunolocalization; Gli3 Western blot; target gene analysis

    PMID:17660199

    Open questions at the time
    • Biochemical mechanism of EVC action between SMO and Gli transcription unknown
    • Whether EVC2 is required in the same step
  11. 2009 High

    Identifying transcriptional activators and repressors of Ihh itself: Atf4 directly binds the Ihh promoter to activate transcription, while δ-EF1 binds intron 1 to repress it—establishing that Ihh expression is tightly controlled by opposing transcription factors.

    Evidence ChIP for Atf4 on Ihh promoter and δ-EF1 on intron 1; respective knockout mice with Ihh expression changes

    PMID:19906842 PMID:19948490

    Open questions at the time
    • Whether Atf4 and δ-EF1 compete or act on independent cell populations
    • Epigenetic regulation of Ihh locus not explored
  12. 2009 High

    Defining PTHrP-dependent vs. -independent IHH functions postnatally: constitutively active PTH1R rescued hypertrophy timing but not proliferation or osteoblast defects in postnatal Ihh-null mice, proving IHH has PTHrP-independent roles in growth plate maintenance.

    Evidence Tamoxifen-inducible postnatal Ihh deletion with Jansen PTH1R transgene rescue

    PMID:19761883

    Open questions at the time
    • Molecular mediators of PTHrP-independent IHH proliferative signaling unidentified
  13. 2009 High

    Linking IHH to brachydactyly type A1 mechanism: the BDA1 E95K mutation reduces IHH binding to PTCH1 and HIP1, diminishing both signaling potency and range, explaining the digit patterning defect.

    Evidence E95K knock-in mice; protein-protein interaction assays for IHH–PTCH1 and IHH–HIP1

    PMID:19252479

    Open questions at the time
    • Whether other BDA1 mutations act through the same binding-affinity mechanism
    • Structural basis of E95K effect unresolved
  14. 2009 High

    Extending IHH function to uterine biology: stromal progesterone receptor drives epithelial IHH expression for implantation, establishing a non-skeletal IHH role.

    Evidence Tissue recombinant grafts with PR-knockout and WT uterine cells under kidney capsule

    PMID:19372202

    Open questions at the time
    • Direct transcription factor binding to Ihh regulatory elements by PR not shown at this stage
  15. 2013 High

    Identifying SPOP as a positive regulator of IHH signaling via Gli3 degradation: SPOP/Cullin-3 ubiquitinates Gli3 repressor, and its loss phenocopies reduced IHH output, adding ubiquitin-proteasome control to the pathway.

    Evidence Spop conditional knockout mice; direct ubiquitination assay; genetic rescue by Gli3 dosage reduction

    PMID:27930311

    Open questions at the time
    • Whether SPOP also targets Gli2 or other pathway components
    • Tissue-specific relevance beyond growth plate not tested
  16. 2014 High

    Completing the Runx2/Cbfβ–Ihh positive feedback loop: Runx2/Cbfβ directly binds and activates the Ihh promoter, closing a feed-forward circuit where IHH induces Runx2 (via Gli2) and Runx2 in turn sustains IHH expression.

    Evidence ChIP and luciferase promoter assay in mesenchymal cells; Cbfβ conditional knockout mice

    PMID:24821091

    Open questions at the time
    • Quantitative contribution of Runx2 vs. Atf4 to Ihh promoter activity not compared
    • Whether this loop operates identically in different skeletal elements
  17. 2017 High

    Revealing additive enhancer architecture: at least nine spatially distinct enhancers regulate IHH dose-dependently, with deletions causing skeletal undergrowth and duplications causing syndactyly and craniosynostosis, establishing regulatory grammar for IHH-related skeletal disease.

    Evidence Transgenic reporter assays and CRISPR deletions/duplications of enhancers in mice

    PMID:28846100

    Open questions at the time
    • Transcription factors binding each enhancer not comprehensively identified
    • Whether enhancer–enhancer interactions occur in 3D chromatin architecture
  18. 2018 High

    Identifying a SOX17-bound distal enhancer for uterine IHH: SOX17 directly binds a −19 kb enhancer co-occupied by PGR, GATA2, and FOXA2, and its CRISPR deletion specifically reduces uterine Ihh expression and impairs implantation.

    Evidence CRISPR-Cas deletion of SOX17-binding enhancer; ChIP-seq for SOX17/PGR/GATA2/FOXA2; uterine-specific Sox17 ablation

    PMID:30356064

    Open questions at the time
    • Whether additional distal enhancers contribute to uterine IHH expression
    • Downstream stromal effectors of uterine IHH signaling not fully defined
  19. 2018 Medium

    Establishing IHH function in ovarian steroidogenesis: granulosa cell-derived IHH regulates theca cell specification, with Ihh knockout causing aberrant steroidogenesis and elevated ovarian inflammation.

    Evidence Dhh and Ihh single and double knockout mice; ovarian transcriptomics; hormonal profiling

    PMID:29788357

    Open questions at the time
    • Mechanism of IHH-dependent theca specification not resolved
    • Single study; inflammatory phenotype not independently confirmed
  20. 2020 Medium

    Uncovering a tumor-suppressive role for IHH in lung: IHH activates canonical hedgehog signaling in lung stroma to suppress adenocarcinoma growth by limiting ROS, distinct from SHH.

    Evidence In vivo CRISPR IHH deletion in KrasG12D/+;Trp53fl/fl mice; ROS scavenger rescue

    PMID:32108165

    Open questions at the time
    • Stromal cell type mediating the effect not identified
    • Mechanism linking hedgehog pathway to ROS suppression unclear
    • Single study in one mouse model
  21. 2024 Medium

    Adding ADGRG6/GPR126 as a growth plate regulator upstream of the IHH–PTHrP axis: Adgrg6 ablation reduces PTHrP but increases IHH signaling, and SMO inhibition rescues the phenotype, supporting PTHrP-independent pro-hypertrophic IHH activity.

    Evidence Conditional Adgrg6 knockout mice; spatial transcriptomics; hedgehog pathway inhibitor rescue

    PMID:39236220

    Open questions at the time
    • How ADGRG6 mechanistically communicates with IHH pathway unknown
    • Single study; spatial transcriptomics findings not independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of IHH–receptor interactions, the identity of PTHrP-independent effectors mediating IHH's proliferative function, the combinatorial logic of the nine-plus enhancer landscape, and how IHH's skeletal, uterine, thymic, and lung-stromal roles are differentially regulated at the transcriptional and post-translational levels.
  • No crystal structure of IHH–PTCH1 complex
  • PTHrP-independent proliferative mediators unidentified
  • Enhancer–transcription factor combinatorics incompletely mapped
  • Tissue-specific pathway modulators not systematically compared

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 5 R-HSA-74160 Gene expression (Transcription) 5
Partners
EVCFOXC1GLI2GLI3HIP1PTCH1RUNX2SMO

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Smoothened (Smo) acts epistatic to Ptc1 to mediate Ihh (and Shh) signaling in the early mouse embryo; Smo/Shh/Ihh compound mutants have identical phenotypes, establishing Smo as the essential transducer of all Hedgehog signals including Ihh. Genetic epistasis analysis; compound mutant mouse embryos (Smo, Shh, Ihh knockouts) Cell High 11440720 11517919
2001 Ihh and BMP signaling act in parallel (not sequentially) to regulate chondrocyte proliferation; BMP signaling does not act as a secondary signal of Ihh to induce PTHrP expression or delay hypertrophic differentiation, but BMP signaling independently modulates Ihh expression levels. Mouse limb explant organ culture with BMP2, PTHrP, Sonic hedgehog, Noggin, cyclopamine; transgenic Ihh-overexpressing mice Development High 11714677
2002 FGF signaling (via FGFR3) accelerates hypertrophic differentiation of chondrocytes and acts antagonistically to BMP signaling in regulating chondrocyte proliferation and Ihh expression; reduced Ihh/PTHrP signaling is a consequence of activating FGFR3 mutations. Limb explant culture with FGF ligands, BMP2, cyclopamine; mouse achondroplasia model; organ culture rescue experiments Developmental cell High 12361605
2004 Ihh is directly required for osteoblast lineage differentiation in the endochondral skeleton; removal of Smo (the Ihh signal transducer) from perichondrial cells prevents bone collar formation, and Smo-null cells fail to contribute to osteoblasts but instead generate ectopic chondrocytes. Cre-LoxP conditional knockout of Smo in perichondrial cells; chimeric embryo analysis; UAS-GAL4 bigenic ectopic Ihh expression; limb-bud cell line cultures Development High 14973297
2004 Heparan sulfate (HS), synthesized by Ext1, regulates the range of Ihh signaling by binding Hedgehog in the extracellular space; reduced HS synthesis in Ext1 hypomorphic mice paradoxically increases the range of Ihh signaling, demonstrating that HS concentration-dependently limits Ihh movement and acts as a long-range morphogen to directly activate PTHrP expression. Hypomorphic Ext1 mutant mice; gene expression analysis; limb skeletal analysis Developmental cell High 15177029
2005 Gli3 acts as a critical repressor downstream of Ihh, mediating two distinct steps of chondrocyte differentiation: (1) the switch from distal to columnar chondrocytes (PTHrP-independent) and (2) the transition from proliferating to hypertrophic chondrocytes (via Gli3-dependent PTHrP expression); removal of Gli3 in Ihh-null embryos restores chondrocyte proliferation and PTHrP expression. Genetic epistasis; Ihh-/-;Gli3-/- double mutant mice; Ihh-overexpressing transgenic mice combined with Gli3 deletion Development High 16141219 16284117
2005 Gli3 is a critical effector of Ihh in the developing skeleton; removal of Gli3 in Ihh-null embryos restores normal chondrocyte proliferation and maturation but only partially rescues osteoblast development and cartilage vascularization, identifying an additional vasculature-derived osteogenic signal that integrates with Ihh. Ihh-/-;Gli3-/- compound mutant mice; histological and molecular analysis Development High 16141219
2006 Wnt9a regulates Indian hedgehog (Ihh) expression temporally and spatially in prehypertrophic chondrocytes through the canonical Wnt/beta-catenin pathway; beta-catenin/Lef1 complex directly binds the Ihh promoter as shown by chromatin immunoprecipitation. Wnt9a knockout mice; double heterozygous Wnt9a;beta-catenin mice; in vivo ChIP of Ihh promoter Development High 16818445
2006 Beta-catenin is required downstream of Ihh signaling and osterix expression for osteoblast differentiation; in chondrocyte survival, beta-catenin acts upstream of Ihh to inhibit chondrocyte apoptosis; Ihh signaling can inhibit chondrocyte hypertrophy and synovial joint formation independently of beta-catenin. Conditional beta-catenin knockout and patched1 gain-of-function in developing endochondral skeleton using floxed alleles; genetic epistasis Development High 16936073
2007 EVC protein localizes to the base of the primary cilium in chondrocytes and is required for transcriptional activation of Ihh target genes (Ptch1, Gli1) downstream of Smo; Gli3 processing is normal in Evc-/- cells, placing EVC between Smo activation and Gli transcriptional output. Evc knockout mice; lacZ reporter; immunolocalization of EVC to primary cilia; in vitro analysis of Evc-/- cells; Western blot for Gli3 processing Development High 17660199
2007 Ihh promotes osteoblast differentiation via Gli2, which upregulates Runx2 expression and enhances its transcriptional activity; Gli2 and Runx2 physically interact (co-immunoprecipitation); Ihh-dependent osteoblast differentiation requires Runx2 as Gli2/Ihh fails to induce ALP in Runx2-deficient cells. Overexpression of Gli2, dominant-negative Gli2 in mesenchymal cells and primary osteoblasts; co-immunoprecipitation of Gli2 and Runx2; Runx2-deficient cell rescue experiments Molecular biology of the cell High 17442891
2007 Ihh directly controls PTHrP expression and chondrocyte morphology in growth region cartilage by signaling directly to chondrocytes (Smo-dependent); demonstrated by tamoxifen-inducible Smo deletion specifically in chondrocytes without affecting perichondrium. Tamoxifen-inducible Col2-Cre to ablate Smo specifically in chondrocytes; molecular analysis of PTHrP expression Developmental biology High 17560974
2009 The BDA1-associated E95K mutation in Ihh impairs interaction of IHH with its receptor PTCH1 and antagonist HIP1, reducing both the potency and range of Ihh signaling; mice carrying the E95K mutation show digit abnormalities consistent with brachydactyly type A1. Mouse model recapitulating E95K mutation; protein-protein interaction assays for IHH-PTCH1 and IHH-HIP1; analysis of signaling range in vivo Nature High 19252479
2009 Atf4 directly binds the Ihh promoter and activates Ihh transcription in chondrocytes; loss of Atf4 markedly reduces Ihh expression, disturbs proliferative zone structure, and pharmacological reactivation of Hh signaling corrects Atf4-/- chondrocyte proliferation defects. Atf4 knockout mice; chromatin immunoprecipitation (Atf4 binding to Ihh promoter); forced Atf4 expression inducing endogenous Ihh mRNA; limb explant culture with Hh agonist rescue Development High 19906842
2009 Ihh signaling is required for postnatal growth plate maintenance via both PTHrP-dependent and PTHrP-independent mechanisms; constitutively active PTH/PTHrP receptor rescues chondrocyte hypertrophy defects but not chondrocyte proliferation or osteoblast defects in postnatal Ihh-null mice. Tamoxifen-inducible postnatal Ihh deletion (Col2-CreER;Ihh(fl/fl)); genetic rescue with constitutively active Jansen PTH/PTHrP receptor transgene Bone High 19761883
2009 Delta-EF1 is an in vivo transcriptional repressor of Ihh; it binds directly to regulatory elements in intron 1 of the Ihh gene in vitro and in vivo (ChIP), and its absence results in increased Ihh expression and delayed hypertrophic differentiation. delta-EF1 knockout mice; electrophoretic mobility shift assay; ChIP of Ihh intron 1; growth plate phenotypic analysis The Journal of cell biology High 19948490
2009 Stromal progesterone receptor (PR) is both necessary and sufficient for progesterone-induced Ihh expression in uterine epithelium, as well as for downstream PTCH1 and NR2F2 induction in stroma; epithelial PR is not required for Ihh induction. Tissue recombinant methodology using PR-knockout and wild-type uterine epithelial and stromal cells grafted under kidney capsule; Ihh mRNA quantification Endocrinology High 19372202
2010 Gli2 acts exclusively as a transcriptional activator (not repressor) in Ihh-dependent osteoblast differentiation; Gli2 repressor function is dispensable for endochondral ossification; in the absence of Gli3, Gli2 activator function alone is sufficient to induce Ihh-dependent osteoblast differentiation. Ihh;Gli2 and Gli3;Gli2 double mutant mice; analysis of osteoblast and chondrocyte differentiation markers Developmental dynamics High 20503377
2011 Chondrocyte-derived Ihh regulates osteoblast differentiation in a paracrine manner; conditioned media from wild-type or Atf4-overexpressing (but not Atf4-null) cartilage corrects osteoblast differentiation defects of Atf4-/- bone marrow stromal cells, and Ihh-blocking antibody eliminates this paracrine effect. Ex vivo cartilage culture conditioned media transfer; Ihh-blocking antibody; genetic rescue with Col2a1-Atf4 transgene in Atf4-null background Development High 22190639
2011 Primary cilia are required for Ihh signal transduction in growth plate chondrocytes in response to hydrostatic compression; disruption of primary cilia with chloral hydrate aborts compression-induced increases in Ihh gene expression and Gli-luciferase reporter activity. Hydrostatic compression system; Gli-luciferase reporter assay; primary cilia disruption with chloral hydrate Bone Medium 21930256
2013 Spop (part of Cullin-3 ubiquitin ligase complex) directly targets the Gli3 repressor for ubiquitination and degradation, thereby positively regulating Ihh signaling; Spop-null mice show upregulation of Gli3 (both full-length and repressor forms) and downregulation of Ihh target genes Ptch1 and Pthlh. Spop conditional knockout mice; ubiquitination assay; Gli3 protein level analysis by western blot; rescue by reducing Gli3 dosage Proceedings of the National Academy of Sciences High 27930311
2013 Ihh signaling interacts with Runx2 and Runx3 during early chondrogenesis; 5E1 antibody-mediated Ihh blockade in mouse embryos inhibits limb bud chondrogenesis and decreases Runx2/Runx3 expression, while exogenous IHH protein increases Runx2 and Runx3; Gli1 directly induces Runx2 and Runx3 transcription. Maternal transfer of 5E1 anti-Ihh antibody to E12.5 embryos; recombinant IHH protein administration; Gli1 transcription factor overexpression PloS one Medium 23383321
2014 The Runx2/Cbfβ complex directly binds putative Runx-binding sites in the Ihh promoter (demonstrated by ChIP and luciferase promoter assay) and upregulates Ihh transcription; Cbfβ deficiency reduces Ihh expression and disrupts the Ihh-PTHrP negative regulatory loop. Mesenchymal stem cell-specific Cbfβ conditional knockout (Prx1-Cre); chromatin immunoprecipitation; luciferase promoter assay Journal of bone and mineral research High 24821091
2015 Foxc1 functions as a transcriptional partner of Gli2 downstream of Ihh signaling; Foxc1 physically interacts with Gli2 (co-immunoprecipitation) and stimulates expression of Ihh target genes including PTHrP and Col10a1; a pathological Foxc1 missense mutation impairs Gli2-Foxc1 association and Ihh function. Microarray identification in vivo; co-immunoprecipitation of Foxc1-Gli2; dominant-negative Foxc1; Foxc1(ch/ch) loss-of-function mouse; Axenfeld-Rieger syndrome mutation functional analysis Nature communications High 25808752
2015 Ihh and PTH1R signaling in limb mesenchyme are both required for proper digit segmentation and phalangeal bone formation; PTH1R signaling rescue via constitutively active allele in Ihh mesenchymal mutants failed to restore digit formation, indicating Ihh uses PTH1R-independent mechanisms in digit development. Prx1-Cre conditional Ihh and PTH1R knockouts; genetic rescue with Jansen constitutively active PTH1R transgene; histological analysis Bone High 26620087
2016 Hand1 transcription factor downregulates Ihh gene expression by inhibiting Runx2 transactivation of the Ihh proximal promoter; genetic overexpression of Hand1 in osteochondral progenitors mimics Ihh loss-of-function phenotype. Transgenic Hand1 overexpression in osteochondral progenitors; in vitro promoter assay (Runx2 transactivation of Ihh promoter inhibited by Hand1) PloS one Medium 26918743
2017 Ihh is regulated by at least nine spatially distinct enhancers acting additively; deletions of enhancers cause dose-dependent growth defects in skull and long bones, while duplications cause dose-dependent upregulation and misexpression of Ihh, leading to syndactyly and craniosynostosis. Transgenic reporter assays in mice; CRISPR/genome editing deletions and duplications of enhancer elements Nature genetics High 28846100
2018 SOX17 regulates IHH expression in uterine epithelium through direct binding to a distal enhancer 19 kb upstream of the Ihh locus; CRISPR-Cas deletion of this SOX17-binding region reduces Ihh expression specifically in the uterus and impairs embryo implantation. Uterine epithelium-specific Sox17 ablation; CRISPR-Cas in vivo deletion of SOX17-binding enhancer; ChIP-seq identifying SOX17, GATA2, FOXA2, PGR co-binding Nature communications High 30356064
2018 IHH and DHH produced by ovarian granulosa cells regulate theca cell specification and steroidogenesis; Ihh single knockout leads to aberrant steroidogenesis and elevated inflammation in ovaries, with greater impact than DHH on Hh pathway activation in the ovary. Dhh and Ihh single and double knockout mice; ovarian transcriptome analysis; hormonal profiling; reproductive fitness assessment Endocrinology Medium 29788357
2019 Ihh promotes terminal differentiation of deep zone chondrocytes in TMJ osteoarthritis via a PTH1R-dependent mechanism; conditional Smo knockout in chondrocytes rescues TMJ OA-like lesions, while Pth1r knockout enhances them; the protective effect of Smo deletion is attenuated by combined Pth1r deletion. Tamoxifen-inducible Col2-CreER conditional Smo and/or Pth1r knockout mice; fluid flow shear stress in vitro model; Ihh inhibitor and PTH1R activator treatment International journal of molecular sciences Medium 31382618
2020 IHH (not SHH) activates the canonical Hedgehog signaling pathway in lung stroma to suppress tumor growth and metastases; in vivo CRISPR deletion of IHH led to more aggressive lung adenocarcinoma growth; the tumor-suppressive mechanism involves limiting reactive oxygen species (ROS). KrasG12D/+;Trp53fl/fl autochthonous murine model; in vivo CRISPR deletion of IHH; anti-SHH/IHH antibody 5E1; ROS scavenger N-acetylcysteine rescue Oncogene Medium 32108165
2022 Ihh in Sp7-expressing osteoblasts promotes osteoblast differentiation and mineralization via the canonical BMP2/Smad/Runx2 pathway; deletion of Ihh in Sp7-expressing cells attenuates this pathway, and defects are rescued by rhBMP2 treatment. Sp7-iCre conditional Ihh knockout mice; primary osteoblast cultures; rhBMP2 rescue; Bmp2/Smad/Runx2 pathway analysis Calcified tissue international Medium 35731246
2024 ADGRG6/GPR126 regulates growth plate homeostasis by controlling PTHrP/IHH signaling; ablation of Adgrg6 reduces PTHrP expression but increases IHH signaling throughout the growth plate, and attenuation of smoothened-dependent Hh signaling restores the expanded hypertrophic zone, confirming that IHH can promote chondrocyte hypertrophy in a PTHrP-independent manner. Col2a1Cre and AcanCreERT2 conditional Adgrg6 knockout mice; spatial transcriptomics on FFPE tissue; hedgehog pathway inhibition rescue Journal of bone and mineral research Medium 39236220
2008 Indian hedgehog (Ihh) both positively and negatively regulates T-cell development in the thymus in a dose-dependent and developmental stage-dependent manner; Ihh produced by DP thymocytes feeds back to negatively regulate differentiation and proliferation of their double-negative progenitors, while promoting the DN-to-DP transition. Ihh knockout and heterozygous mice; thymus explant cultures with recombinant Hh protein; Rag-/-;Ihh+/- and conditional Ihh knockout adult mice; cell population analysis Blood Medium 19109233
2002 Ihh enhances chondrocyte differentiation through its N-terminal signaling domain, and a missense mutation (W160G) in the N-terminal domain reduces differentiation-inducing capacity; Ihh signaling functionally antagonizes PTHrP-mediated PKA activation, while PTHrP antagonizes Ihh-mediated differentiation through a PKA-dependent mechanism via PTHR1. Overexpression of Ihh, N-Ihh, and W160G mutant in CFK-2 chondrocytic cells; constitutively active PTHR1 (H223R); recombinant N-Shh treatment; alkaline phosphatase and collagen assays Journal of cell science Medium 12082161

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. Development (Cambridge, England) 365 11714677
2002 Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. Developmental cell 348 12361605
2004 Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton. Development (Cambridge, England) 333 14973297
2001 Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R symmetry by the mouse node. Cell 241 11517919
2001 Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node. Cell 224 11440720
2004 Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Developmental cell 220 15177029
1999 Interaction of Ihh and BMP/Noggin signaling during cartilage differentiation. Developmental biology 193 10328918
2006 Wnt9a signaling is required for joint integrity and regulation of Ihh during chondrogenesis. Development (Cambridge, England) 169 16818445
2006 Wnt/beta-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation. Development (Cambridge, England) 160 16936073
1995 Cloning, expression, and chromosomal location of SHH and IHH: two human homologues of the Drosophila segment polarity gene hedgehog. Genomics 159 7590746
2007 Evc is a positive mediator of Ihh-regulated bone growth that localises at the base of chondrocyte cilia. Development (Cambridge, England) 154 17660199
2005 Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development. Development (Cambridge, England) 146 16141219
2007 Ihh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function. Molecular biology of the cell 144 17442891
2001 A Ser(365)-->Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia. Human molecular genetics 124 11181569
2005 Gli3 acts as a repressor downstream of Ihh in regulating two distinct steps of chondrocyte differentiation. Development (Cambridge, England) 112 16284117
2011 IGF-1R signaling in chondrocytes modulates growth plate development by interacting with the PTHrP/Ihh pathway. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 106 21312270
2009 Atf4 regulates chondrocyte proliferation and differentiation during endochondral ossification by activating Ihh transcription. Development (Cambridge, England) 105 19906842
2003 Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips. American journal of human genetics 101 12632327
2017 Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog). Nature genetics 98 28846100
2004 Characterization of the human nasal embryonic LHRH factor gene, NELF, and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism (IHH). Journal of human genetics 89 15362570
2009 A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range. Nature 83 19252479
2007 Tamoxifen-inducible gene deletion reveals a distinct cell type associated with trabecular bone, and direct regulation of PTHrP expression and chondrocyte morphology by Ihh in growth region cartilage. Developmental biology 79 17560974
2017 Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism (IHH). European journal of endocrinology 77 28882981
2018 SOX17 regulates uterine epithelial-stromal cross-talk acting via a distal enhancer upstream of Ihh. Nature communications 74 30356064
2010 Copy-number variations involving the IHH locus are associated with syndactyly and craniosynostosis. American journal of human genetics 73 21167467
2006 Neuroendocrine, gonadal, placental, and obstetric phenotypes in patients with IHH and mutations in the G-protein coupled receptor, GPR54. Molecular and cellular endocrinology 73 16757106
2012 The ankyrin-repeat transmembrane protein BDA1 functions downstream of the receptor-like protein SNC2 to regulate plant immunity. Plant physiology 72 22740615
2005 Absence of IHH and retention of PTHrP signalling in enchondromas and central chondrosarcomas. The Journal of pathology 68 15685701
2015 The transcription factor Foxc1 is necessary for Ihh-Gli2-regulated endochondral ossification. Nature communications 64 25808752
2011 Primary cilia modulate Ihh signal transduction in response to hydrostatic loading of growth plate chondrocytes. Bone 62 21930256
2002 Expression and localization of Indian hedgehog (Ihh) and parathyroid hormone related protein (PTHrP) in the human growth plate during pubertal development. The Journal of endocrinology 62 12176676
2018 BMP-IHH-mediated interplay between mesenchymal stem cells and osteoclasts supports calvarial bone homeostasis and repair. Bone research 61 30345151
2016 Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling. Proceedings of the National Academy of Sciences of the United States of America 59 27930311
2009 Stromal progesterone receptors mediate induction of Indian Hedgehog (IHH) in uterine epithelium and its downstream targets in uterine stroma. Endocrinology 59 19372202
2018 IHH Gene Mutations Causing Short Stature With Nonspecific Skeletal Abnormalities and Response to Growth Hormone Therapy. The Journal of clinical endocrinology and metabolism 53 29155992
2008 Indian hedgehog (Ihh) both promotes and restricts thymocyte differentiation. Blood 49 19109233
2013 Ihh and Runx2/Runx3 signaling interact to coordinate early chondrogenesis: a mouse model. PloS one 48 23383321
2012 The human hepatocyte cell lines IHH and HepaRG: models to study glucose, lipid and lipoprotein metabolism. Archives of physiology and biochemistry 46 22594799
2019 Inhibition of Ihh Reverses Temporomandibular Joint Osteoarthritis via a PTH1R Signaling Dependent Mechanism. International journal of molecular sciences 45 31382618
2011 Chondrocytic Atf4 regulates osteoblast differentiation and function via Ihh. Development (Cambridge, England) 42 22190639
2013 Sirt6 regulates postnatal growth plate differentiation and proliferation via Ihh signaling. Scientific reports 40 24149372
2014 Core binding factor beta (Cbfβ) controls the balance of chondrocyte proliferation and differentiation by upregulating Indian hedgehog (Ihh) expression and inhibiting parathyroid hormone-related protein receptor (PPR) expression in postnatal cartilage and bone formation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 38 24821091
2021 MicroRNA-223 restricts liver fibrosis by inhibiting the TAZ-IHH-GLI2 and PDGF signaling pathways via the crosstalk of multiple liver cell types. International journal of biological sciences 36 33867837
2006 The PTHrP-Ihh feedback loop in the embryonic growth plate allows PTHrP to control hypertrophy and Ihh to regulate proliferation. Biomechanics and modeling in mechanobiology 35 16691414
2018 Roles of Ihh signaling in chondroprogenitor function in postnatal condylar cartilage. Matrix biology : journal of the International Society for Matrix Biology 33 29447948
2013 A GDF5 point mutation strikes twice--causing BDA1 and SYNS2. PLoS genetics 33 24098149
2014 Evolutionary genomics and adaptive evolution of the Hedgehog gene family (Shh, Ihh and Dhh) in vertebrates. PloS one 32 25549322
2010 Gli2 activator function in preosteoblasts is sufficient to mediate Ihh-dependent osteoblast differentiation, whereas the repressor function of Gli2 is dispensable for endochondral ossification. Developmental dynamics : an official publication of the American Association of Anatomists 32 20503377
2008 MSX2 stimulates chondrocyte maturation by controlling Ihh expression. The Journal of biological chemistry 32 18682398
2009 Partial rescue of postnatal growth plate abnormalities in Ihh mutants by expression of a constitutively active PTH/PTHrP receptor. Bone 31 19761883
2003 Secondary chondrocyte-derived Ihh stimulates proliferation of periosteal cells during chick development. Development (Cambridge, England) 31 12925598
2002 A novel mutation in the IHH gene causes brachydactyly type A1: a 95-year-old mystery resolved. Human genetics 31 12384778
2018 Identification of Variants in RET and IHH Pathway Members in a Large Family With History of Hirschsprung Disease. Gastroenterology 30 29601828
2002 Growth defect in Grg5 null mice is associated with reduced Ihh signaling in growth plates. Developmental dynamics : an official publication of the American Association of Anatomists 29 11984876
2006 A novel heterozygous mutation in the Indian hedgehog gene (IHH) is associated with brachydactyly type A1 in a Chinese family. Journal of human genetics 26 16871364
2005 Developmentally regulated expression of Shh and Ihh in the developing mouse cranial base: comparison with Sox9 expression. The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology 26 16145660
2005 Can the growth factors PTHrP, Ihh and VEGF, together regulate the development of a long bone? Journal of biomechanics 25 16298375
2017 Regulation of Calvarial Osteogenesis by Concomitant De-repression of GLI3 and Activation of IHH Targets. Frontiers in physiology 24 29311969
2014 Wnt7b can replace Ihh to induce hypertrophic cartilage vascularization but not osteoblast differentiation during endochondral bone development. Bone research 24 26273517
2007 Changes in serotoninergic receptors 1A and 2A in the piglet brainstem after intermittent hypercapnic hypoxia (IHH) and nicotine. Brain research 24 17451658
2002 Distribution and quantification of NMDA R1 mRNA and protein in the piglet brainstem and effects of intermittent hypercapnic hypoxia (IHH). Brain research 24 12270508
2018 Reproductive, Physiological, and Molecular Outcomes in Female Mice Deficient in Dhh and Ihh. Endocrinology 23 29788357
2017 MicroRNA-467g inhibits new bone regeneration by targeting Ihh/Runx-2 signaling. The international journal of biochemistry & cell biology 23 28163186
2016 Naringin promotes osteogenic differentiation of bone marrow stromal cells by up-regulating Foxc2 expression via the IHH signaling pathway. American journal of translational research 23 27904711
2019 HAS3-induced extracellular vesicles from melanoma cells stimulate IHH mediated c-Myc upregulation via the hedgehog signaling pathway in target cells. Cellular and molecular life sciences : CMLS 22 31820036
2014 TMJ degeneration in SAMP8 mice is accompanied by deranged Ihh signaling. Journal of dental research 22 24453178
2002 Ihh enhances differentiation of CFK-2 chondrocytic cells and antagonizes PTHrP-mediated activation of PKA. Journal of cell science 22 12082161
2020 Stromal Hedgehog pathway activation by IHH suppresses lung adenocarcinoma growth and metastasis by limiting reactive oxygen species. Oncogene 21 32108165
2012 Comparative functional analysis of two fibroblast growth factor receptor 1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in isolated hypogonadotropic hypogonadism (IHH). Gene 21 23276709
2009 delta-EF1 is a negative regulator of Ihh in the developing growth plate. The Journal of cell biology 21 19948490
2017 Effects of Melatonin on Early Pregnancy in Mouse: Involving the Regulation of StAR, Cyp11a1, and Ihh Expression. International journal of molecular sciences 20 28749439
2016 Transfection of the IHH gene into rabbit BMSCs in a simulated microgravity environment promotes chondrogenic differentiation and inhibits cartilage aging. Oncotarget 20 27802423
2014 Mesenchymal stem cells overexpressing Ihh promote bone repair. Journal of orthopaedic surgery and research 20 25346272
2011 Ihh signaling regulates mandibular symphysis development and growth. Journal of dental research 20 21297010
2014 Fetal jaw movement affects Ihh signaling in mandibular condylar cartilage development: the possible role of Ihh as mechanotransduction mediator. Archives of oral biology 19 25033382
2019 Expression of Ihh signaling pathway in condylar cartilage after bite-raising in adult rats. Journal of molecular histology 18 31302828
2016 The Transcription Factor Hand1 Is Involved In Runx2-Ihh-Regulated Endochondral Ossification. PloS one 18 26918743
2020 Effect of total flavonoids of Rhizoma Drynariae in thiram induced cytotoxicity of chondrocyte via BMP-2/Runx2 and IHH/PTHrP expressions. Ecotoxicology and environmental safety 17 32866894
2017 The inhibitory roles of Ihh downregulation on chondrocyte growth and differentiation. Experimental and therapeutic medicine 17 29434683
2021 Association of sonic hedgehog signaling pathway genes IHH, BOC, RAB23a and MIR195-5p, MIR509-3-5p, MIR6738-3p with gastric cancer stage. Scientific reports 16 33811245
2017 Curcumin Inhibits Chondrocyte Hypertrophy of Mesenchymal Stem Cells through IHH and Notch Signaling Pathways. Chemical & pharmaceutical bulletin 16 28768930
2019 Fluoride regulates the expression of extracellular matrix HSPG and related signaling pathways FGFR3 and Ihh/PTHrP feedback loop during endochondral ossification. Environmental toxicology and pharmacology 15 31731208
2009 Brachydactyly type A1 associated with unusual radiological findings and a novel Arg158Cys mutation in the Indian hedgehog (IHH) gene. European journal of medical genetics 15 19464397
2009 Missense mutations in IHH impair Indian Hedgehog signaling in C3H10T1/2 cells: Implications for brachydactyly type A1, and new targets for Hedgehog signaling. Cellular & molecular biology letters 15 20024692
2006 The expression of Hedgehog genes (Ihh, Dhh) and Hedgehog target genes (Ptc1, Gli1, Coup-TfII) is affected by estrogenic stimuli in the uterus of immature female rats. Toxicology and applied pharmacology 15 17109907
2012 A large duplication involving the IHH locus mimics acrocallosal syndrome. European journal of human genetics : EJHG 14 22234151
2022 Altered Expression of the Hedgehog Pathway Proteins BMP2, BMP4, SHH, and IHH Involved in Knee Cartilage Damage of Patients With Osteoarthritis and Kashin-Beck Disease. Cartilage 13 35313742
2022 Inactivation of Ihh in Sp7-Expressing Cells Inhibits Osteoblast Proliferation, Differentiation, and Bone Formation, Resulting in a Dwarfism Phenotype with Severe Skeletal Dysplasia in Mice. Calcified tissue international 13 35731246
2016 Absence of collagen IX accelerates hypertrophic differentiation in the embryonic mouse spine through a disturbance of the Ihh-PTHrP feedback loop. Cell and tissue research 13 27666725
2013 The Ihh signal is essential for regulating proliferation and hypertrophy of cultured chicken chondrocytes. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 13 23928032
2021 Type II collagen from squid cartilage mediated myogenic IGF-I and irisin to activate the Ihh/PThrp and Wnt/β-catenin pathways to promote fracture healing in mice. Food & function 12 34080588
2015 Ihh and PTH1R signaling in limb mesenchyme is required for proper segmentation and subsequent formation and growth of digit bones. Bone 12 26620087
2023 Reproductive Phenotypes and Genotypes in Men With IHH. The Journal of clinical endocrinology and metabolism 11 36268624
2020 Combined deletions of IHH and NHEJ1 cause chondrodystrophy and embryonic lethality in the Creeper chicken. Communications biology 11 32214226
2007 IHH and FGF8 coregulate elongation of digit primordia. Biochemical and biophysical research communications 11 17889828
2020 Clinical and Molecular Description of 16 Families With Heterozygous IHH Variants. The Journal of clinical endocrinology and metabolism 10 32311039
2011 The expressions of the SOX trio, PTHrP (parathyroid hormone-related peptide)/IHH (Indian hedgehog protein) in surgically induced osteoarthritis of the rat. Cell biology international 10 21073445
2009 VEGF and IHH rescue definitive hematopoiesis in Gata-4 and Gata-6-deficient murine embryoid bodies. Experimental hematology 10 19501129
2024 The G protein-coupled receptor ADGRG6 maintains mouse growth plate homeostasis through IHH signaling. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 9 39236220
2022 Exogenous growth hormone functionally alleviates glucocorticoid-induced longitudinal bone growth retardation in male rats by activating the Ihh/PTHrP signaling pathway. Molecular and cellular endocrinology 9 35063477