Affinage

SHH

Sonic hedgehog protein · UniProt Q15465

Round 2 corrected
Length
462 aa
Mass
49.6 kDa
Annotated
2026-04-28
130 papers in source corpus 46 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SHH encodes Sonic hedgehog, a secreted morphogen that is proteolytically processed into an N-terminal signaling fragment dually modified by N-palmitoylation (Cys-24) and C-terminal cholesterol, with the lipid-modified multimeric form showing greatly enhanced signaling potency and forming long-range gradients in vivo (PMID:7720571, PMID:9593755, PMID:11395778). SHH binds the receptor PTCH1 (and co-receptors BOC, GAS1, CDON), de-repressing Smoothened to activate GLI transcription factors—GLI2 primarily as an activator and GLI3 as a repressor—with pathway amplitude tuned by negative feedback through PTCH1 upregulation, HIP-mediated ligand sequestration, LRP2-dependent endocytic clearance, and O-GlcNAcylation of GLI2 (PMID:8906787, PMID:10050855, PMID:26439398, PMID:35969743). This signaling axis controls dorsoventral neural tube patterning, anteroposterior limb patterning via the zone of polarizing activity, forebrain midline development, cerebellar granule neuron expansion, intestinal villus formation, blood–brain barrier integrity, and hair follicle stem cell specification, while also mediating non-canonical axon guidance through BOC/Numb/Dock/ELMO/Rac1 cytoskeletal remodeling (PMID:8269518, PMID:21658586, PMID:35132078, PMID:22144466, PMID:26771489, PMID:30078728, PMID:31054872). Heterozygous loss-of-function mutations in SHH cause autosomal dominant holoprosencephaly (HPE3), and aberrant ligand-driven SHH pathway activation drives basal cell carcinoma, medulloblastoma, and digestive tract tumors (PMID:8896572, PMID:9115210, PMID:14520413, PMID:14520411).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1993 High

    The identity of the ZPA polarizing signal had been unknown for decades; demonstration that Shh is expressed in the ZPA and sufficient to induce mirror-image digit duplications established Shh as the long-sought anteroposterior limb patterning morphogen.

    Evidence In situ hybridization and retroviral misexpression/grafting in chick limb buds

    PMID:8269518

    Open questions at the time
    • Mechanism of long-range gradient formation not addressed
    • Downstream transcriptional effectors unknown at this point
  2. 1994 High

    How Shh generates a signaling-competent fragment was resolved by showing that the precursor undergoes autoproteolytic cleavage, with the N-terminal product retaining all signaling activity.

    Evidence Expression cloning, Western blot of cleavage products, chick limb grafting

    PMID:7720571

    Open questions at the time
    • Post-translational lipid modifications not yet identified
    • Receptor identity still unknown
  3. 1996 High

    Identification of the Shh receptor was achieved by showing that Patched binds Shh with high affinity and forms a complex with Smoothened, which itself does not bind Shh, establishing the two-component receptor architecture.

    Evidence Binding assays and co-immunoprecipitation

    PMID:8906787

    Open questions at the time
    • How Ptch de-represses Smo mechanistically was unknown
    • Co-receptors not identified
  4. 1996 High

    The question of whether SHH mutations cause human disease was answered by identifying heterozygous loss-of-function SHH mutations in families with autosomal dominant holoprosencephaly (HPE3), proving SHH haploinsufficiency disrupts forebrain midline development.

    Evidence Mutational analysis and sequencing in multiple HPE families

    PMID:8896571 PMID:8896572

    Open questions at the time
    • Genotype–phenotype variability not mechanistically explained
    • Enhancer-level regulation of Shh in forebrain not yet characterized
  5. 1997 High

    Whether excess Shh signaling could directly cause cancer was demonstrated by K14-SHH transgenic mice developing basal cell carcinomas, establishing Shh as an oncogenic driver in skin.

    Evidence Transgenic mouse overexpression with histological tumor analysis

    PMID:9115210

    Open questions at the time
    • Ligand-dependent vs. ligand-independent pathway activation in tumors not distinguished
    • Contribution of stromal vs. epithelial Shh signaling unclear
  6. 1998 High

    The basis for Shh's signaling potency was explained by discovery that the processed N-terminal fragment carries dual lipid modifications—N-palmitoylation at Cys-24 and C-terminal cholesterol—with the dual-modified form ~30-fold more potent than unmodified protein.

    Evidence Mass spectrometry, peptide mapping, cell-based alkaline phosphatase potency assay

    PMID:9593755

    Open questions at the time
    • The enzyme responsible for Shh palmitoylation (later identified as HHAT) not known at this time
    • How lipid modifications affect gradient formation not resolved
  7. 1998 High

    Downstream transcriptional mediation of Shh signaling was clarified by showing that Gli2 and Gli3 cooperate with functional redundancy in Shh-dependent tooth development, with double mutants completely lacking normal dentition.

    Evidence Gli2/Gli3 single and double mutant mouse analysis with ectopic protein application

    PMID:9655803

    Open questions at the time
    • Relative activator vs. repressor roles of individual Gli proteins not yet delineated
  8. 1999 High

    How the Shh pathway is attenuated after activation was addressed by discovery of Hip, a membrane protein that binds Shh with Ptc-comparable affinity and is itself a transcriptional target of the pathway, establishing negative feedback by ligand sequestration.

    Evidence Binding assays, in situ hybridization showing Shh-dependent Hip induction, transgenic overexpression phenocopy

    PMID:10050855

    Open questions at the time
    • Relative contributions of Hip vs. Ptch1 to gradient shaping not quantified
  9. 2001 High

    The physical form of Shh that mediates long-range signaling was identified as a freely diffusible, cholesterol-modified multimer forming a measurable gradient across the limb bud, with Ptch and Hip jointly regulating its distribution.

    Evidence Biochemical fractionation, gradient sedimentation, in vivo gradient detection in chick limb

    PMID:11395778

    Open questions at the time
    • Mechanisms of multimerization and release from producing cells not resolved
    • Role of cytonemes or exosomal transport not addressed
  10. 2002 High

    The epistatic relationship between Shh and Gli3 in limb patterning was resolved: Shh−/−;Gli3−/− double mutants form distal skeletal elements but lack digit identity, showing Shh functions primarily by modulating the Gli3 activator/repressor ratio rather than being required for limb outgrowth per se.

    Evidence Double-mutant mouse genetic analysis with skeletal preparations

    PMID:12198547

    Open questions at the time
    • How different Gli3 A/R ratios specify individual digit identities mechanistically unclear
  11. 2002 High

    A long-range cis-regulatory element (ZRS) ~1 Mb from SHH in the LMBR1 intron was found to drive ZPA-specific SHH expression; point mutations in the ZRS cause ectopic anterior Shh and polydactyly in humans, revealing extreme-distance enhancer regulation of SHH.

    Evidence Translocation mapping, transgene insertion site identification, human family segregation analysis

    PMID:12032320 PMID:12837695

    Open questions at the time
    • Chromatin topology mediating 1 Mb enhancer–promoter contact not characterized
    • Other tissue-specific enhancers not systematically mapped
  12. 2003 High

    Ligand-dependent Shh signaling was established as a driver of multiple epithelial cancers beyond skin, including pancreatic adenocarcinoma, digestive tract tumors, and small-cell lung cancer, with cyclopamine and Hh-neutralizing antibodies suppressing tumor growth in vitro and in vivo.

    Evidence Transgenic Pdx-Shh mice, cyclopamine treatment, neutralizing antibodies, xenograft regression assays across multiple tumor types

    PMID:12629553 PMID:14520411 PMID:14520413

    Open questions at the time
    • Relative contributions of autocrine vs. paracrine Shh signaling in tumor vs. stroma not fully dissected
    • Whether all tumors require ongoing ligand or have downstream mutations unclear
  13. 2003 High

    The question of how Gli2 and Gli3 divide labor in Shh-dependent somite patterning was answered: Gli2 acts primarily as activator and Gli3 as repressor, but each protein exhibits dual functions and preferentially regulates distinct target gene subsets.

    Evidence Double-mutant mouse analysis and adenoviral Gli overexpression in presomitic mesoderm explants

    PMID:14602680

    Open questions at the time
    • Chromatin-level basis for target gene selectivity not identified
  14. 2003 High

    A non-neuronal role of Shh was established by showing that astrocyte-derived Shh signals to BBB endothelial cells expressing Hh receptors, promoting barrier formation and immune quiescence by suppressing proinflammatory mediators and leukocyte migration.

    Evidence Genetic inactivation in endothelial cells, pharmacological Hh inhibition, in vitro BBB and leukocyte migration assays

    PMID:22144466

    Open questions at the time
    • Whether BBB-Shh axis is therapeutically targetable in neuroinflammatory disease not tested
    • Relative contribution of Shh vs. other Hh ligands not determined
  15. 2009 High

    How Shh expression is confined to the ZPA was explained by identification of a BMP→Shh negative feedback loop: BMP inhibits FGF/Wnt-mediated Shh maintenance via MAPK, restricting Shh transcription spatially.

    Evidence BMP bead implantation, pathway inhibitors, cycloheximide treatment, in situ hybridization in chick limb

    PMID:19855020

    Open questions at the time
    • Transcription factors mediating BMP repression of Shh not identified
  16. 2014 High

    GATA6 was identified as a direct transcriptional repressor of Shh in anterior limb mesenchyme; conditional GATA6 loss caused ectopic anterior Shh and polydactyly rescued by Shh deletion, establishing GATA6 as a spatial gatekeeper of Shh expression.

    Evidence ChIP in limb bud chromatin, conditional knockout, genetic rescue

    PMID:24415953

    Open questions at the time
    • Whether GATA6 cooperates with ZRS-mediated regulation unclear
  17. 2014 High

    The co-receptor BOC was shown to associate with PTCH1 in cerebellar granule neuron precursors and amplify Shh-driven DNA damage and Ptch1 LOH, promoting medulloblastoma progression; Boc inactivation reduced tumorigenesis.

    Evidence Boc knockout mouse model, CyclinD1 epistasis, DNA damage quantification in medulloblastoma

    PMID:25263791

    Open questions at the time
    • Whether other co-receptors (GAS1, CDON) similarly promote DNA damage not tested
  18. 2015 High

    Quantitative in vivo measurement of the Shh gradient in neural tube explained pathway adaptation: transcriptional upregulation of inhibitory Ptch1, downregulation of Gli expression, and differential Gli2 stability collectively dampen signaling despite increasing ligand concentration.

    Evidence Quantitative imaging, computational modeling, Gli2 protein analysis

    PMID:25833741

    Open questions at the time
    • Post-translational modifications governing Gli stability not fully catalogued
  19. 2015 High

    LRP2 was found to function as a context-dependent Shh receptor—promoting signaling in forebrain but mediating endocytic clearance of Shh in retina, protecting the retinal margin niche from excess mitogenic stimulation.

    Evidence LRP2 conditional knockout mouse, SHH clearance assays, proliferation analysis

    PMID:26439398

    Open questions at the time
    • Structural basis for LRP2's dual function not resolved
  20. 2018 High

    The effector cascade for Shh-mediated axon guidance was delineated: Shh stimulation causes Dock3/4–ELMO1/2 dissociation from BOC, ELMO translocation to growth cone periphery, and Rac1 activation, linking non-canonical Shh signaling to cytoskeletal remodeling.

    Evidence Co-immunoprecipitation of Dock/ELMO with Boc, Rac1 activation assay, in vivo axon guidance analysis

    PMID:30078728

    Open questions at the time
    • Whether this non-canonical pathway operates in contexts beyond commissural axon guidance is unknown
  21. 2019 High

    BOC was established as an endocytic platform gating Ptch1 internalization: Shh induces Numb-dependent Boc internalization into early endosomes, which is required for subsequent Ptch1 internalization and growth-cone turning; Shh–Ptch1 binding alone is insufficient.

    Evidence Co-IP of Numb–Boc, endosome colocalization imaging, growth cone turning assays, in vivo commissural axon guidance

    PMID:31054872

    Open questions at the time
    • Whether Numb-dependent endocytosis operates in canonical Shh signaling contexts not determined
  22. 2019 High

    A prechordal plate enhancer (SBE7) was shown to be essential for Shh expression in rostral axial mesoderm and ventral forebrain, with its deletion causing holoprosencephaly-like craniofacial defects, providing a cis-regulatory basis for the HPE phenotype.

    Evidence Targeted enhancer deletion in mice, in situ hybridization, craniofacial phenotyping

    PMID:31685615

    Open questions at the time
    • Whether SBE7 variants contribute to reduced-penetrance HPE in humans not tested
  23. 2022 High

    A new layer of Gli regulation was uncovered: OGT O-GlcNAcylates Gli2 at Ser355, promoting its deacetylation and transcriptional activation by displacing p300; OGT ablation extends survival in a medulloblastoma model, identifying a druggable node in Shh-driven tumors.

    Evidence O-GlcNAcylation site mapping/mutagenesis, co-IP with p300, Gli2 reporter assays, OGT conditional KO and chemical inhibition in medulloblastoma mouse model

    PMID:35969743

    Open questions at the time
    • Whether O-GlcNAcylation of Gli2 operates in non-tumor developmental contexts not examined
    • Other PTMs on Gli2 that interact with this modification unknown
  24. 2022 High

    An intercompartmental Wnt→Shh→mesenchyme circuit was established in intestinal villus formation, where epithelial Wnt signaling induces Shh expression and secreted Shh acts on subepithelial mesenchymal cells to drive morphogenesis.

    Evidence Single-cell transcriptomics, organoid co-culture, genetic Wnt/Shh pathway manipulation

    PMID:35132078

    Open questions at the time
    • Whether this circuit is reactivated in intestinal regeneration or colorectal cancer is unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive characterization of Shh signaling, several first-order mechanistic questions remain: the structural basis for how dual lipid-modified Shh multimers traverse tissue distances, the complete catalogue of tissue-specific cis-regulatory elements and their 3D chromatin interactions, and whether non-canonical Shh signaling (BOC/Numb/Dock/Rac1) operates broadly outside axon guidance.
  • Mechanism of long-range lipid-modified multimer transport not resolved
  • Full enhancer landscape and chromatin topology at the SHH locus not characterized
  • Scope of non-canonical Shh signaling beyond axon guidance unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-1266738 Developmental Biology 12 R-HSA-1643685 Disease 10 R-HSA-162582 Signal Transduction 6
Partners
BOCGLI2GLI3HHIPLRP2NUMBPTCH1SMO

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Sonic hedgehog (Shh) is expressed specifically in the zone of polarizing activity (ZPA) of the limb bud and is sufficient to polarize limbs when ectopically expressed, inducing mirror-image digit duplications and activating Hox genes, establishing Shh as the ZPA signal for anteroposterior limb patterning. In situ hybridization, grafting experiments, retroviral misexpression in chick limb buds Cell High 8269518
1994 The murine Shh (Hhg-1) protein is proteolytically cleaved into two stable fragments from a single precursor; the N-terminal fragment retains signaling activity. Shh is expressed in notochord, ventral neural tube, and posterior limb bud mesenchyme and can induce digit duplications when ectopically grafted. Expression cloning, Western blot of cleavage products, chick limb grafting assays, transgenic Drosophila expression Development High 7720571
1996 Patched (Ptc/PTCH) binds Sonic hedgehog protein with high affinity and forms a physical complex with Smoothened (Smo/SMO), which does not itself bind Shh directly, establishing Ptch as the Shh receptor and Smo as a signaling component linked to Ptch. Binding assays, co-immunoprecipitation, expression cloning Nature High 8906787
1996 Heterozygous loss-of-function mutations in human SHH (including premature termination and missense mutations altering conserved residues near the alpha-helix-1 motif or signal cleavage site) cause autosomal dominant holoprosencephaly (HPE3), demonstrating that SHH haploinsufficiency disrupts forebrain midline development. Mutational analysis of HPE families, sequencing, chromosomal rearrangement mapping Nature genetics High 8896571 8896572
1997 Overexpression of Sonic hedgehog in mouse skin (K14-SHH transgenic mice) is sufficient to induce basal cell carcinomas and other features of basal cell nevus syndrome, demonstrating that excess Shh signaling can drive skin tumorigenesis. Transgenic mouse overexpression with histological analysis Science High 9115210
1998 Human Sonic hedgehog is palmitoylated on the alpha-amino group of Cys-24 (the N-terminus of the processed signaling fragment) in addition to the cholesterol modification at its C-terminus. The dual-lipid-modified form shows ~30-fold greater potency than unmodified soluble Shh in a C3H10T1/2 alkaline phosphatase induction assay. Mass spectrometry, peptide mapping/sequencing, cell-free palmitoylation assay with radioactive palmitate, cell-based potency assay The Journal of Biological Chemistry High 9593755
1998 Shh is expressed in tooth epithelium and, upon ectopic application to mandibular mesenchyme, induces Ptc and Gli1 expression; Gli2 and Gli3 mediate Shh signaling in tooth development, with Gli2/Gli3 double mutants failing to form any normal teeth, revealing functional redundancy of downstream Gli genes. Whole-mount in situ hybridization, ectopic protein application to explants, genetic mutant analysis (Gli2-/-, Gli3-/-, double mutants) Development High 9655803
1999 Hedgehog-interacting protein (Hip) is a membrane glycoprotein that binds all three mammalian Hedgehog proteins (including Shh) with affinity comparable to Ptc-1. Hip expression is induced by Shh signaling and its overexpression in cartilage phenocopies loss of Indian hedgehog function, establishing Hip as a negative feedback regulator that attenuates Hh signaling by ligand binding. Binding assays, in situ hybridization, transgenic overexpression in cartilage with skeletal phenotype analysis Nature High 10050855
1999 In mice, FGF8 acts as a left determinant while Sonic hedgehog is required to prevent left-determining signals from being expressed on the right side, demonstrating that Shh and FGF8 have opposing and context-specific roles in left-right axis determination that differ from those in chick. Genetic loss-of-function analysis in mouse embryos (Fgf8 and Shh mutants), in situ hybridization for laterality markers Science High 10411502
2001 A freely diffusible, cholesterol-modified, multimeric form of Shh (s-ShhNp) exists in vivo and forms a gradient across the chick limb anterior-posterior axis. Its availability is regulated by two pathway antagonists, Patched and Hip, demonstrating that long-range Shh signaling is mediated by this soluble multimeric species. Biochemical fractionation, gradient sedimentation, chick limb gradient detection, genetic manipulation of Ptc and Hip Nature High 11395778
2001 Sonic hedgehog induces the expansion of primitive human hematopoietic stem cells through a mechanism dependent on downstream BMP-4 signaling; anti-Shh antibodies block cytokine-induced proliferation, and Noggin (BMP-4 inhibitor) phenocopies anti-Shh but does not affect BMP-4-induced proliferation directly, placing Shh upstream of BMP-4 in this pathway. Antibody neutralization, Noggin inhibition, in vivo repopulation assay in immunodeficient mice Nature immunology High 11175816
2002 Genetic analysis of Shh-/-;Gli3-/- double mutant mice shows that Shh and Gli3 are dispensable for formation of distal limb skeletal elements per se but are required for digit identity; Shh's effects on skeletal patterning are necessarily mediated through Gli3 by regulating the balance of Gli3 transcriptional activator versus repressor activities. Double-mutant mouse genetic analysis, skeletal preparations, in situ hybridization Nature High 12198547
2002 A long-range cis-acting regulatory element (ZRS), located within intron 5 of the Lmbr1 gene ~1 Mb from Shh, drives Shh expression in the ZPA limb bud; disruption of this element (by translocation or transgene insertion) causes preaxial polydactyly through ectopic anterior Shh expression, and point mutations in ZRS segregate with polydactyly in multiple human families. Genetic mapping, identification of translocation breakpoints and transgene insertion sites, in situ hybridization, family segregation analysis Human molecular genetics / Proceedings of the National Academy of Sciences High 12032320 12837695
2003 Sonic hedgehog is aberrantly expressed in pancreatic adenocarcinoma and its precursor lesions (PanIN); misexpression of Shh in pancreatic endoderm (Pdx-Shh mice) produces PanIN-like lesions with K-ras mutations; cyclopamine-mediated Hh pathway inhibition induces apoptosis and blocks proliferation in pancreatic cancer cell lines in vitro and in vivo. Transgenic mouse model, immunohistochemistry, cyclopamine pharmacological inhibition, in vitro and xenograft assays Nature High 14520413
2003 A wide range of digestive tract tumors (esophagus, stomach, biliary tract, pancreas) display Hh pathway activity driven by endogenous Shh/Ihh ligand expression; pathway inhibition by cyclopamine or Hh-neutralizing antibody suppresses tumor cell growth in vitro and causes xenograft regression in vivo, demonstrating ligand-dependent autocrine/paracrine Hh signaling in these cancers. Cyclopamine treatment, Hh-neutralizing antibody, Hh ligand stimulation, xenograft tumor regression Nature High 14520411
2003 Gli2 and Gli3 are required for Shh-dependent sclerotome induction; Gli2 primarily acts as an activator and Gli3 primarily as a repressor, but both proteins exhibit dual activator/repressor functions in the somite; individual Gli proteins preferentially activate distinct subsets of Shh target genes, dividing Shh patterning, growth, and feedback functions between different Gli proteins. Double-mutant mouse analysis, in vitro somite explant assays, adenoviral Gli overexpression in presomitic mesoderm Development High 14602680
2003 Astrocytes in the developing and adult CNS secrete Sonic hedgehog, blood-brain barrier endothelial cells express Hh receptors, and Hh pathway activity promotes BBB formation/integrity and immune quiescence by decreasing endothelial proinflammatory mediator expression and leukocyte adhesion/migration. Pharmacological inhibition of Hh pathway, genetic inactivation in endothelial cells, in vitro BBB assays, in vivo leukocyte migration assays Science High 22144466
2003 Hedgehog signaling is activated within the airway epithelium during repair of acute injury and in developing pulmonary neuroendocrine precursors; small-cell lung cancers maintain ligand-dependent (Shh) Hh pathway activation for their malignant phenotype, as cyclopamine treatment inhibits SCLC growth in vitro and in vivo. In situ hybridization, pharmacological cyclopamine inhibition, SCLC xenograft assays Nature High 12629553
2006 FGF9 signals from the mesothelium and epithelium to regulate SHH signaling in lung mesenchyme; FGF9 maintains SHH pathway activity in the sub-epithelial mesenchyme to control cell proliferation, survival, and expression of mesenchymal-to-epithelial signals, and also represses smooth muscle differentiation. Fgf9 loss-of-function and inducible gain-of-function mouse models, in situ hybridization, proliferation assays Development High 16540513
2007 Ftm (Rpgrip1l) localizes to the ciliary basal body and is required for Shh signaling in vertebrates; loss of Ftm alters the ratio of Gli3 activator to Gli3 repressor, affecting neural tube and limb patterning. Ftm is not essential for cilia assembly but is required for full Shh response, identifying it as a cilium-related Hh signaling component specific to vertebrates. Subcellular localization by immunofluorescence, genetic mutant analysis in mice, Gli3 isoform analysis by Western blot Development High 17553904
2007 Protease nexin 1 (PN-1/SERPINE2) interacts with LRP receptors to antagonize SHH-induced cerebellar granule neuron precursor (CGNP) proliferation; PN-1/LRP interaction interferes with SHH-induced cyclin D1 expression and inhibits GLI1 transcriptional activity. PN-1-deficient CGNPs show enhanced basal proliferation, overactivation of the Shh pathway, and delayed differentiation in vivo. Co-immunoprecipitation/binding assay, PN-1 knockout mouse analysis, Gli1 reporter assays, proliferation assays Development High 17409116
2008 Sonic hedgehog drives desmoplasia in pancreatic cancer by promoting differentiation and motility of pancreatic stellate cells and fibroblasts; blocking SHH with a neutralizing antibody in orthotopic mouse models reduces tumor-associated desmoplasia. SHH overexpression in transformed pancreatic cell line, anti-SHH blocking antibody in orthotopic xenograft, stellate cell assays Clinical cancer research High 18829478
2008 Acquisition of granule neuron precursor (CGNP) identity is a critical determinant of competence to form Shh-induced medulloblastoma; oncogenic Hh signaling in a spectrum of CNS progenitors generates medulloblastoma only when cells acquire CGNP identity, and neoplastic cells in human and mouse medulloblastoma retain embryonic granule lineage features. Cell-type-specific Cre-mediated Hh pathway activation in multiple progenitor populations, lineage tracing, immunohistochemistry Cancer cell High 18691547
2009 BMP activity negatively regulates Shh transcription in the limb bud, forming a BMP-Shh negative-feedback loop that confines Shh expression to the ZPA; BMP downregulates Shh by interfering with FGF- and Wnt-mediated Shh maintenance; FGF induction of Shh requires protein synthesis and is mediated by the ERK1/2 MAPK pathway. BMP bead implantation, BMP inhibition, FGF inhibition, ERK pathway inhibitors, cycloheximide treatment, in situ hybridization Development High 19855020
2009 YAP1 is upregulated in human medulloblastomas with aberrant Shh signaling; Shh induces YAP1 expression and promotes YAP1 nuclear localization in CGNPs; YAP1 drives CGNP proliferation, identifying it as a Shh effector in cerebellar development and medulloblastoma. Human tumor analysis, Shh treatment of primary CGNPs, YAP1 overexpression proliferation assays, immunofluorescence Genes & development High 19952108
2010 Foxa2 directly binds genomic regions of Gli2 and represses its expression at the transcriptional level; Foxa2 and Foxa1 attenuate Shh signaling in ventral midbrain progenitors by inhibiting Gli2 expression, while also acting as upstream positive regulators of Shh expression, thus both positively and negatively regulating the pathway. Chromatin immunoprecipitation (ChIP), conditional knockout mouse analysis (Wnt1cre;Foxa2flox/flox), gain/loss-of-function studies Mechanisms of development High 21093585
2011 Lhx6 and Lhx8 transcription factors coexpressed in early-born MGE neurons directly regulate a Shh enhancer to induce neuronal Shh expression; Shh from MGE neurons then acts non-cell-autonomously on overlying progenitors to maintain Lhx6, Lhx8, and Nkx2-1 expression and promote generation of late-born somatostatin+ and parvalbumin+ cortical interneurons. Conditional genetic Shh deletion in MGE mantle zone, Shh enhancer reporter assay, in situ hybridization, immunofluorescence Neuron High 21658586
2011 Shh signaling from the epithelium blocks miR-206 expression in airway smooth muscle (ASM), which in turn de-represses BDNF protein translation; this Shh/miR-206/BDNF cascade coordinates ASM innervation with ASM formation during lung branching morphogenesis. Genetic Shh pathway manipulation (chemical and genetic), miR-206 overexpression/knockdown, BDNF protein measurement, lung explant analyses The Journal of Neuroscience High 22031887
2014 GATA6 binds to chromatin at Shh and Gli1 regulatory elements in limb buds and, working synergistically with FOG co-factors, represses Shh expression in the anterior limb mesenchyme; conditional loss of GATA6 causes ectopic anterior Shh expression and hindlimb polydactyly rescued by simultaneous Shh deletion. ChIP in limb bud chromatin, conditional knockout mice (Prx1-Cre;GATA6flox/flox), luciferase reporter assays, genetic rescue with Shh conditional deletion PLoS genetics High 24415953
2014 Boc (a Shh co-receptor) associates with Ptch1 to mediate Shh signaling in cerebellar granule cell precursors; Boc elevation increases Shh-driven DNA damage via CyclinD1, promoting Ptch1 loss of heterozygosity and medulloblastoma progression; Boc inactivation reduces tumor progression. Boc knockout mouse model, medulloblastoma xenografts, CyclinD1 epistasis analysis, DNA damage quantification Developmental cell High 25263791
2014 Arx directly binds a Shh floor plate enhancer (SFPE2) together with FoxA2 to induce Shh expression in the floor plate; Shh then activates Nkx2.2, which in turn suppresses Arx, creating a negative feedback loop that regulates Shh levels in the spinal cord floor plate. In ovo chick electroporation (gain-of-function), Arx-deficient mouse analysis (loss-of-function), enhancer binding assay Developmental biology High 24968361
2015 LRP2 acts as a context-dependent SHH receptor: in the forebrain it promotes SHH signaling, but in the developing retina it mediates endocytic clearance of SHH to antagonize morphogen action and protect the retinal margin progenitor niche from mitogenic stimuli; loss of LRP2 expands the retinal progenitor pool. LRP2 conditional knockout mouse analysis, immunofluorescence, proliferation assays, SHH clearance assays Developmental cell High 26439398
2015 Ptch2 mediates the Shh response in Ptch1-/- cells; the Shh response in Ptch1-/- cells remains ligand-dependent and can be inhibited by Shh-blocking antibody; dominant-negative Ptch2 expression in chick neural tube activates Shh signaling, while Ptch1-/-;Ptch2-/- cells cannot further activate the Shh response, demonstrating that Ptch2 functionally suppresses Shh signaling when Ptch1 is absent. Ptch1/Ptch2 double-knockout cell analysis, Shh-blocking antibody, dominant-negative constructs in chick neural tube electroporation, chemotaxis assays Development High 25085974
2015 Quantitative analysis of the Shh gradient in mouse neural tube reveals that pathway adaptation (decrease in Gli activity despite increasing Shh gradient) is driven by multiple mechanisms: transcriptional upregulation of inhibitory Ptch1, downregulation of Gli protein expression, and differential stability of active vs. inactive Gli isoforms. Different cell types show distinct signaling dynamics due to differential Gli2 regulation. Quantitative imaging of Shh gradient in vivo, computational pathway modeling, Gli2 protein expression analysis, pathway stimulation downstream of Ptch1 Nature communications High 25833741
2015 Shh and Netrin-1 synergize to guide commissural axons toward the floor plate; combined shallow gradients of both cues polarize Src-family kinase (SFK) activity in growth cones and enable axon turning at gradient steepnesses insufficient for either cue alone, identifying SFKs as integrators of the two guidance cues. Microfluidic in vitro gradient assay, dissociated commissural neuron turning assay, SFK activity imaging PLoS biology High 25826604
2015 Eya1 phosphatase, acting with the DNA-binding protein Six1, promotes Shh target gene expression by regulating Gli transcriptional activators; shRNA screen identified Eya1 as a positive Shh pathway regulator, and catalytically active Eya1 is required for Shh-dependent hindbrain growth and medulloblastoma tumor growth. shRNA phosphatome screen, Eya1 knockout analysis in hindbrain, medulloblastoma growth assays, Gli reporter assays Developmental cell High 25816987
2016 In developing hair buds, asymmetric cell divisions produce WNT-low daughters that respond to paracrine SHH and symmetrically expand as stem cells, while basal WNT-high daughters express but do not respond to SHH and remain slow-cycling progenitors, demonstrating a niche-independent mechanism for stem cell specification through differential WNT/SHH signaling. Immunofluorescence, live imaging, lineage tracing, in utero lentiviral transduction, cell-cycle analyses, conditional genetics Cell High 26771489
2016 Foxf2 in the palatal mesenchyme (downstream of Shh) represses Fgf18 expression; loss of Foxf2 causes ectopic Fgf18 expression that in turn inhibits Shh expression in the palatal epithelium, revealing a Shh→Foxf→Fgf18→Shh negative-feedback circuit in palate development. Cre/loxP tissue-specific knockout, RNA-seq, WISH, FGF18 protein addition to palatal explants PLoS genetics High 26745863
2018 Shh-mediated commissural axon guidance requires Dock3/4 GEFs and their binding partners ELMO1/2 as effectors; Dock/ELMO interact with the Shh receptor Boc and this interaction is reduced upon Shh stimulation; Shh stimulation translocates ELMO to the growth cone periphery and activates Rac1, linking non-canonical Shh signaling to cytoskeletal remodeling. shRNA knockdown, in vivo axon guidance analysis, co-immunoprecipitation of Dock/ELMO with Boc, Rac1 activation assay, ELMO localization imaging Developmental cell High 30078728
2019 Shh induces Boc internalization into early endosomes via the endocytic adaptor Numb, which binds Boc; Numb-dependent Boc internalization is required for Ptch1 internalization and growth-cone turning; Shh binding to Ptch1 alone is insufficient for Ptch1 internalization, demonstrating that Boc functions as a Shh-dependent endocytic platform gating Ptch1 internalization and non-canonical Shh axon guidance signaling. Co-immunoprecipitation of Numb-Boc, endosome colocalization imaging, Numb knockdown, in vitro growth cone turning assays, in vivo commissural axon guidance Neuron High 31054872
2019 A prechordal plate enhancer (SBE7) located near known forebrain Shh enhancers drives Shh expression in the prechordal plate and overlying ventral forebrain midline; deletion of SBE7 from the mouse genome markedly reduces Shh expression in rostral axial mesoderm and ventral forebrain/hypothalamus, causing holoprosencephaly-like craniofacial abnormalities. Enhancer identification, targeted genomic deletion in mice, in situ hybridization, craniofacial phenotype analysis Proceedings of the National Academy of Sciences High 31685615
2022 O-GlcNAc transferase (OGT) O-GlcNAcylates Gli2 at Ser355, which promotes Gli2 deacetylation and transcriptional activation via dissociation from the acetyltransferase p300, thereby activating Shh signaling in granule neuron precursors; OGT ablation or chemical inhibition improves survival in a medulloblastoma mouse model. O-GlcNAcylation site mapping, mutagenesis, co-IP with p300, Gli2 transcriptional reporter assays, OGT conditional knockout and chemical inhibition in medulloblastoma mouse model Proceedings of the National Academy of Sciences High 35969743
2022 Wnt signaling in small intestinal epithelium directly regulates Shh expression; epithelial Shh then acts on subepithelial mesenchymal cells to drive villus formation, establishing a mesenchymal-epithelial Wnt→Shh→mesenchyme circuit essential for anterior-posterior regionalisation of the small intestine. Single-cell transcriptomics of mesenchyme, intestinal organoid co-culture, genetic Wnt pathway manipulation, Shh pathway inhibition Nature communications High 35132078
2020 In a mouse model of chemotherapy-induced alopecia (CIA), downregulation of Shh signaling in the hair matrix is a critical early event; MAPK pathway activation upstream suppresses Shh; recombinant Shh protein partially rescues hair loss; inhibition of Shh signaling alone recapitulates key CIA features, establishing the MAPK-Shh axis as a key mechanism in CIA. Mouse CIA model, phosphoproteomics, recombinant Shh rescue, genetic/pharmacological Shh pathway inhibition, human hair follicle organ culture Journal of Investigative Dermatology High 32682910

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 1994 8269518
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2003 Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 1214 14520413
2003 Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 1062 14520411
1996 The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 935 8906787
2003 A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Human molecular genetics 916 12837695
1996 Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nature genetics 894 8896572
2003 Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 891 12629553
2005 Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution. Science (New York, N.Y.) 881 15790807
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science (New York, N.Y.) 652 22144466
1999 Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 623 10050855
2014 Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer cell 598 24651015
1998 Identification of a palmitic acid-modified form of human Sonic hedgehog. The Journal of biological chemistry 584 9593755
1997 Basal cell carcinomas in mice overexpressing sonic hedgehog. Science (New York, N.Y.) 563 9115210
2008 Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer cell 515 18691547
1996 Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nature genetics 510 8896571
2001 Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nature immunology 490 11175816
2007 Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem cells (Dayton, Ohio) 484 17628016
2002 Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature 470 12198547
2007 Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proceedings of the National Academy of Sciences of the United States of America 439 17392427
2004 Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proceedings of the National Academy of Sciences of the United States of America 438 15314219
2008 Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 434 18829478
2011 Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta neuropathologica 403 21267586
2002 Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proceedings of the National Academy of Sciences of the United States of America 367 12032320
2001 A freely diffusible form of Sonic hedgehog mediates long-range signalling. Nature 364 11395778
2005 Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. Journal of proteome research 350 16335952
2000 The sonic hedgehog-patched-gli pathway in human development and disease. American journal of human genetics 332 11001584
2009 YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes & development 325 19952108
1998 The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants. Development (Cambridge, England) 294 9655803
2011 Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer. Cancer research 289 21975935
1999 The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Human molecular genetics 282 10556296
1994 Products, genetic linkage and limb patterning activity of a murine hedgehog gene. Development (Cambridge, England) 271 7720571
1999 Differences in left-right axis pathways in mouse and chick: functions of FGF8 and SHH. Science (New York, N.Y.) 249 10411502
2006 FGF9 and SHH signaling coordinate lung growth and development through regulation of distinct mesenchymal domains. Development (Cambridge, England) 178 16540513
2007 Ftm is a novel basal body protein of cilia involved in Shh signalling. Development (Cambridge, England) 163 17553904
2000 Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma. Genes, chromosomes & cancer 154 10564585
2019 Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma. Nature 148 31664194
2016 WNT-SHH Antagonism Specifies and Expands Stem Cells prior to Niche Formation. Cell 135 26771489
2013 Specified neural progenitors sort to form sharp domains after noisy Shh signaling. Cell 133 23622240
2019 Preformed chromatin topology assists transcriptional robustness of Shh during limb development. Proceedings of the National Academy of Sciences of the United States of America 125 31147463
2011 Lhx6 and Lhx8 coordinately induce neuronal expression of Shh that controls the generation of interneuron progenitors. Neuron 124 21658586
2003 Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome induction. Development (Cambridge, England) 123 14602680
2015 Ptch1 and Gli regulate Shh signalling dynamics via multiple mechanisms. Nature communications 120 25833741
2019 Developmentally regulated Shh expression is robust to TAD perturbations. Development (Cambridge, England) 118 31511252
2003 The emergent design of the neural tube: prepattern, SHH morphogen and GLI code. Current opinion in genetics & development 100 14550418
2014 Tumor-associated macrophages in SHH subgroup of medulloblastomas. Clinical cancer research : an official journal of the American Association for Cancer Research 94 25344580
1999 Sonic hedgehog (shh) expression in developing and regenerating axolotl limbs. The Journal of experimental zoology 91 10404648
1997 Shh expression in developing and regenerating limb buds of Xenopus laevis. Developmental dynamics : an official publication of the American Association of Anatomists 86 9186057
2016 A Shh-Foxf-Fgf18-Shh Molecular Circuit Regulating Palate Development. PLoS genetics 78 26745863
2021 The transcriptional landscape of Shh medulloblastoma. Nature communications 73 33741928
2009 A BMP-Shh negative-feedback loop restricts Shh expression during limb development. Development (Cambridge, England) 71 19855020
2011 A Shh/miR-206/BDNF cascade coordinates innervation and formation of airway smooth muscle. The Journal of neuroscience : the official journal of the Society for Neuroscience 70 22031887
2010 Direct and indirect requirements of Shh/Gli signaling in early pituitary development. Developmental biology 69 20934421
2014 Mapping the Shh long-range regulatory domain. Development (Cambridge, England) 68 25252942
2004 Induction and specification of midbrain dopaminergic cells: focus on SHH, FGF8, and TGF-beta. Cell and tissue research 64 15322912
2006 Solitary median maxillary central incisor (SMMCI) syndrome. Orphanet journal of rare diseases 62 16722608
1998 Overlapping and non-overlapping Ptch2 expression with Shh during mouse embryogenesis. Mechanisms of development 61 9858693
2000 The role of cholesterol in Shh signaling and teratogen-induced holoprosencephaly. Cellular and molecular life sciences : CMLS 59 11130177
2020 An SGLT2 inhibitor modulates SHH expression by activating AMPK to inhibit the migration and induce the apoptosis of cervical carcinoma cells. Cancer letters 57 32931885
2015 Integration of shallow gradients of Shh and Netrin-1 guides commissural axons. PLoS biology 53 25826604
2004 Expression of Sonic hedgehog (SHH) signaling molecules in ameloblastomas. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 53 15128061
2010 Foxa1 and Foxa2 positively and negatively regulate Shh signalling to specify ventral midbrain progenitor identity. Mechanisms of development 52 21093585
2020 The SHH/GLI signaling pathway: a therapeutic target for medulloblastoma. Expert opinion on therapeutic targets 51 32990091
2000 Control of Shh activity and signaling in the neural tube. Developmental dynamics : an official publication of the American Association of Anatomists 51 11002335
2016 The many lives of SHH in limb development and evolution. Seminars in cell & developmental biology 49 26762695
2014 The Shh receptor Boc promotes progression of early medulloblastoma to advanced tumors. Developmental cell 48 25263791
2015 LRP2 Acts as SHH Clearance Receptor to Protect the Retinal Margin from Mitogenic Stimuli. Developmental cell 44 26439398
2005 Constitutive activation of the shh-ptc1 pathway by a patched1 mutation identified in BCC. Oncogene 43 15592520
2014 GATA6 is a crucial regulator of Shh in the limb bud. PLoS genetics 42 24415953
2022 Mesenchymal-epithelial crosstalk shapes intestinal regionalisation via Wnt and Shh signalling. Nature communications 40 35132078
2014 Ptch2 mediates the Shh response in Ptch1-/- cells. Development (Cambridge, England) 40 25085974
2015 The Eya1 phosphatase promotes Shh signaling during hindbrain development and oncogenesis. Developmental cell 38 25816987
2003 Patterning the limb before and after SHH signalling. Journal of anatomy 37 12587914
2005 Epithelial expression of SHH signaling pathway in odontogenic tumors. Oral oncology 36 16376138
2022 O-GlcNAcylation promotes cerebellum development and medulloblastoma oncogenesis via SHH signaling. Proceedings of the National Academy of Sciences of the United States of America 35 35969743
2016 MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma. Endocrine-related cancer 35 26825960
2012 Epigenetic changes in Basal Cell Carcinoma affect SHH and WNT signaling components. PloS one 35 23284750
2010 Expression of SHH signaling pathway components in the developing human lung. Histochemistry and cell biology 35 20821230
2020 The hedgehog co-receptor BOC differentially regulates SHH signaling during craniofacial development. Development (Cambridge, England) 34 33060130
2007 Sequential and cooperative action of Fgfs and Shh in the zebrafish retina. Developmental biology 33 18177854
2019 SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization. Proceedings of the National Academy of Sciences of the United States of America 32 31685615
2016 Role of Sonic Hedgehog (Shh) Signaling in Bladder Cancer Stemness and Tumorigenesis. Current urology reports 32 26757905
2018 Polarized Dock Activity Drives Shh-Mediated Axon Guidance. Developmental cell 31 30078728
2016 A Cascade of Wnt, Eda, and Shh Signaling Is Essential for Touch Dome Merkel Cell Development. PLoS genetics 31 27414798
2015 Cranial nerve development requires co-ordinated Shh and canonical Wnt signaling. PloS one 31 25799573
2019 Boc Acts via Numb as a Shh-Dependent Endocytic Platform for Ptch1 Internalization and Shh-Mediated Axon Guidance. Neuron 30 31054872
2015 Interaction of sonic hedgehog (SHH) pathway with cancer stem cell genes in gastric cancer. Medical oncology (Northwood, London, England) 30 25636508
2020 Dysregulated Kras/YY1/ZNF322A/Shh transcriptional axis enhances neo-angiogenesis to promote lung cancer progression. Theranostics 29 32929330
2019 Triptonide inhibits lung cancer cell tumorigenicity by selectively attenuating the Shh-Gli1 signaling pathway. Toxicology and applied pharmacology 29 30610878
2020 ZC4H2 stabilizes RNF220 to pattern ventral spinal cord through modulating Shh/Gli signaling. Journal of molecular cell biology 28 31336385
2007 Protease nexin 1 and its receptor LRP modulate SHH signalling during cerebellar development. Development (Cambridge, England) 28 17409116
2016 An Fgf-Shh signaling hierarchy regulates early specification of the zebrafish skull. Developmental biology 27 27060628
2016 Rx3 and Shh direct anisotropic growth and specification in the zebrafish tuberal/anterior hypothalamus. Development (Cambridge, England) 27 27317806
2014 Transcriptional profiles of SHH pathway genes in keratocystic odontogenic tumor and ameloblastoma. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 27 24930892
2009 Shh and Pax6 have unconventional expression patterns in embryonic morphogenesis in Sepia officinalis (Cephalopoda). Gene expression patterns : GEP 27 19683074
1996 The linear organization of cell columns in human and nonhuman anthropoid Tpt cortex. Anatomy and embryology 27 8800420
2020 Inhibition of Shh Signaling through MAPK Activation Controls Chemotherapy-Induced Alopecia. The Journal of investigative dermatology 26 32682910
2014 Arx together with FoxA2, regulates Shh floor plate expression. Developmental biology 25 24968361
2020 Berberine inhibits colorectal tumor growth by suppressing SHH secretion. Acta pharmacologica Sinica 24 32958873
2019 Principles of tumorigenesis and emerging molecular drivers of SHH-activated medulloblastomas. Annals of clinical and translational neurology 24 31139698
2016 Potential role of Shh-Gli1-BMI1 signaling pathway nexus in glioma chemoresistance. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 24 27662839
2011 Heparanase Modulates Shh and Wnt3a Signaling in Human Medulloblastoma Cells. Experimental and therapeutic medicine 24 21442027
2022 CGRP and Shh Mediate the Dental Pulp Cell Response to Neuron Stimulation. Journal of dental research 23 35403480
2019 Genomic architecture of Shh-dependent cochlear morphogenesis. Development (Cambridge, England) 23 31488567
2014 The role of the SHH gene in prostate cancer cell resistance to paclitaxel. The Prostate 22 24925370
2021 Dysfunction of Shh signaling activates autophagy to inhibit trophoblast motility in recurrent miscarriage. Experimental & molecular medicine 21 33390589
2021 The effects of TPT and dietary quercetin on growth, hepatic oxidative damage and apoptosis in zebrafish. Ecotoxicology and environmental safety 21 34450426
2019 Mesenchymal Sufu Regulates Development of Mandibular Molars via Shh Signaling. Journal of dental research 21 31499014
2012 Duration of Shh signaling contributes to mDA neuron diversity. Developmental biology 21 23201023
2004 Loss of Gli3 and Shh function disrupts olfactory axon trajectories. The Journal of comparative neurology 21 15065125
2020 Thyroid disruption and developmental toxicity caused by triphenyltin (TPT) in zebrafish embryos/larvae. Toxicology and applied pharmacology 20 32173372
2018 Medulloblastoma, WNT-activated/SHH-activated: clinical impact of molecular analysis and histogenetic evaluation. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 20 29582169
2016 Rescue Effects and Underlying Mechanisms of Intragland Shh Gene Delivery on Irradiation-Induced Hyposalivation. Human gene therapy 20 27021743
2013 Bmp and Shh signaling mediate the expression of satb2 in the pharyngeal arches. PloS one 20 23555697
2013 Midline-derived Shh regulates mesonephric tubule formation through the paraxial mesoderm. Developmental biology 20 24370450
2010 A cascade of irx1a and irx2a controls shh expression during retinogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 20 21046643
2024 Developmental basis of SHH medulloblastoma heterogeneity. Nature communications 19 38191555
2019 EIF5A regulates proliferation and chemoresistance in pancreatic cancer through the sHH signalling pathway. Journal of cellular and molecular medicine 19 30761741
2012 Apicoplast triose phosphate transporter (TPT) gene knockout is lethal for Plasmodium. Molecular and biochemical parasitology 19 23041242
2021 Identification of disease-relevant modulators of the SHH pathway in the developing brain. Development (Cambridge, England) 18 34463328
2019 The Shh receptor Boc is important for myelin formation and repair. Development (Cambridge, England) 18 31048318
2018 Upstream Enhancer Elements of Shh Regulate Oral and Dental Patterning. Journal of dental research 17 29481312
2005 Gli3 mutation rescues the generation, but not the differentiation, of oligodendrocytes in Shh mutants. Brain research 17 16336945
2022 Toosendanin inhibits colorectal cancer cell growth through the Hedgehog pathway by targeting Shh. Drug development research 16 35656621
2019 Sonic hedgehog (Shh) and CC chemokine ligand 2 signaling pathways in asthma. Journal of the Chinese Medical Association : JCMA 16 31058710
2019 QKI deficiency maintains glioma stem cell stemness by activating the SHH/GLI1 signaling pathway. Cellular oncology (Dordrecht, Netherlands) 16 31292920
2010 Expression of Sonic hedgehog (SHH) and CDX2 in the columnar epithelium of the lower oesophagus. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 16 20619754
2000 Are triphalangeal thumb-polysyndactyly syndrome (TPTPS) and tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS) identical? A father with TPTPS and his daughter with THPTTS in a Thai family. American journal of medical genetics 16 10869115