PTCH2 Gene

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gene3361 wordssynced 2026-04-02

PTCH2 Gene

Overview

The PTCH2 gene (Patched 2) encodes a transmembrane receptor that serves as the primary negative regulator of Hedgehog (Hh) signaling. As one of two patched homologs in mammals (along with PTCH1), PTCH2 plays essential roles in embryonic development, tissue patterning, stem cell maintenance, and cellular homeostasis. The Hedgehog signaling pathway is one of the most fundamental developmental pathways, and its dysregulation is implicated in multiple cancers and developmental disorders.

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PTCH2 Gene

Overview

In the nervous system, PTCH2-mediated Hedgehog signaling regulates neural tube patterning, neuronal differentiation, oligodendrocyte development, and adult neurogenesis.[@wang2020] While PTCH2 has somewhat weaker repressive activity compared to PTCH1, it fulfills essential tissue-specific functions, particularly in the central nervous system.
<div class="infobox infobox-gene">
<table>
<tr><th>Gene Symbol</th><td>PTCH2</td></tr>
<tr><th>Gene Name</th><td>Patched 2</td></tr>
<tr><th>Chromosome</th><td>1p34.1</td></tr>
<tr><th>NCBI Gene ID</th><td><a href="https://www.ncbi.nlm.nih.gov/gene/9603" target="_blank">9603</a></td></tr>
<tr><th>OMIM</th><td><a href="https://www.omim.org/entry/607349" target="_blank">607349</a></td></tr>
<tr><th>UniProt</th><td><a href="https://www.uniprot.org/uniprot/Q9Y2L9" target="_blank">Q9Y2L9</a></td></tr>
<tr><th>Ensembl ID</th><td><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000117425" target="_blank">ENSG00000117425</a></td></tr>
<tr><th>Associated Diseases</th><td>Basal Cell Carcinoma, Gorlin Syndrome, Medulloblastoma, Alzheimer's Disease</td></tr>
</table>
</div>

Gene Structure and Protein Architecture

Genomic Organization

The PTCH2 gene spans approximately 37 kb on chromosome 1p34.1 and consists of 23 exons encoding a protein of 1,207 amino acids with a molecular weight of approximately 134 kDa.

Protein Domains

PTCH2 is a multipass transmembrane protein with characteristic features:

12 transmembrane domains: Organized in two clusters of six, characteristic of the NPC1 family

Large extracellular loops: Bind Hedgehog ligands

Intracellular C-terminal tail: Contains regulatory sequences

Sterol-sensing domain (SSD): Shared with NPC1 and NPC2 proteins, important for SMO repression

Mermaid diagram (expand to render)

Biological Functions

Hedgehog Signal Transduction

PTCH2 regulates the Hh pathway through:

SMO repression: In the absence of Hh ligands, PTCH2 actively represses Smoothened (SMO) activity through the sterol-sensing domain (SSD)

Ligand binding: When Hh ligands (SHH, IHH, DHH) bind, PTCH2 undergoes conformational change and releases SMO

Signal activation: Uninhibited SMO activates GLI transcription factors through a series of phosphorylation events

Target gene regulation: GLI proteins control genes involved in proliferation, differentiation, and patterning

The regulation of SMO by PTCH2 involves direct protein-protein interaction and cholesterol trafficking. PTCH2 controls the cholesterol content of the SMO-containing membrane microdomains, thereby regulating SMO activity.

Signaling Pathway Details

The Hedgehog signaling cascade involves multiple steps:

Receptor Complex Formation:

PTCH2 forms homodimers on the cell surface
Interacts with cell surface heparan sulfate proteoglycans
Binds Hedgehog ligands with high affinity

SMO Activation Mechanism:

PTCH2 removal relieves SMO inhibition
SMO undergoes conformational changes
SMO accumulates in primary cilia
Downstream effectors are recruited

GLI Activation:

PKA, CK1, and GSK3β phosphorylate GLI
Full-length GLI is processed to truncated form
Active GLI translocates to nucleus
Target gene transcription ensues

Neural Development

PTCH2-mediated Hh signaling in the nervous system:

Neural tube patterning: Establishes ventral-dorsal gradients in the spinal cord through morphogen signaling

Neuronal differentiation: Promotes specific neuronal fates in developing brain

Oligodendrocyte development: Regulates oligodendrocyte precursor cell specification and maturation

Cerebellar development: Critical for cerebellar granule neuron precursor proliferation

Forebrain development: Important for cortical and hippocampal development

Adult Neurogenesis

In the adult brain, PTCH2 participates in:

Subventricular zone neurogenesis: Regulates neural stem cell activity and neuroblast production

Hippocampal neurogenesis: Influences dentate gyrus neural progenitors and survival

Oligodendrocyte regeneration: Controls oligodendrocyte precursor cell behavior and remyelination

Axon regeneration: May play roles in neural repair after injury

PTCH1 vs PTCH2 Comparison

PTCH1 and PTCH2 have distinct and overlapping functions:

| Feature | PTCH1 | PTCH2 |
|---------|-------|-------|
| Expression | Ubiquitous | Tissue-enriched |
| Repression strength | Stronger | Weaker |
| Developmental role | Major | Minor/modulatory |
| Adult function | Housekeeping | Specialized |
| Disease relevance | Tumor suppressor | Context-dependent |

Disease Associations

Basal Cell Carcinoma

PTCH2 acts as a tumor suppressor with distinct roles from PTCH1:

Loss-of-function mutations: Contribute to BCC development. PTCH2 mutations account for approximately 10-15% of sporadic BCC cases, often in combination with PTCH1 alterations.

Synergy with PTCH1: Both paralogs can contribute to tumor suppression. In some tumors, combined PTCH1 and PTCH2 dysfunction leads to more aggressive phenotypes.

SMO activation: Uninhibited SMO drives tumorigenesis through constitutive hedgehog pathway activation.

Mutation spectrum: PTCH2 mutations in BCC are predominantly truncating mutations that abrogate receptor function.

Therapeutic implications: BCC patients with PTCH2 mutations may respond to SMO inhibitors like vismodegib.

Gorlin Syndrome (Nevoid Basal Cell Carcinoma Syndrome)

While primarily associated with PTCH1, PTCH2 mutations can also contribute:

Multi-tumor predisposition: Increased risk of BCC, medulloblastoma, and other Hh-driven tumors.

Developmental abnormalities: Jaw keratocysts, skeletal anomalies including bifid ribs and vertebral abnormalities.

Phenotype variability: PTCH2 mutations in Gorlin syndrome may lead to milder phenotypes compared to PTCH1.

Genetic counseling: Families with Gorlin syndrome should consider PTCH2 testing when PTCH1 testing is negative.

Medulloblastoma

PTCH2 alterations in medulloblastoma:

SHH subgroup: Hh-driven medulloblastomas involve PTCH2 alterations in approximately 10% of cases.

Therapeutic targeting: SMO inhibitors effective in PTCH2-altered cases, though resistance mechanisms develop.

Prognostic significance: PTCH2 alterations may be associated with intermediate prognosis in SHH-subgroup medulloblastoma.

Pediatric relevance: PTCH2 mutations are more common in pediatric than adult medulloblastoma.

Alzheimer's Disease

Emerging evidence links PTCH2 to AD:

Hedgehog signaling in AD: Reduced Hh signaling in AD brains. Studies show decreased SHH and PTCH2 expression in AD hippocampus.

Neuronal survival: PTCH2 supports neuronal resilience through anti-apoptotic mechanisms. Hh signaling promotes neuronal survival under stress conditions.

Amyloid interaction: Aβ affects Hh pathway components including PTCH2. In vitro studies show Aβ treatment reduces PTCH2 expression.

Potential therapy: Hh pathway activation may have neuroprotective effects. SMO agonists are being explored for AD treatment.

Synaptic function: Hh signaling regulates synaptic plasticity and memory formation, processes compromised in AD.

Parkinson's Disease

Emerging connections to PD:

Dopaminergic neurons: Hh signaling influences dopaminergic neuron development and maintenance.

Alpha-synuclein: Interactions between Hh pathway and α-synuclein pathology are being investigated.

Neuroinflammation: Hh signaling modulates microglial activation and neuroinflammation.

Therapeutic potential: Hh pathway modulators may protect dopaminergic neurons.

Multiple Sclerosis

PTCH2 connections to demyelinating diseases:

Oligodendrocyte development: Hh signaling critical for oligodendrocyte precursor cell (OPC) maturation.

Remyelination: Hh pathway activation promotes remyelination in animal models.

Demyelination: PTCH2 expression is altered in MS lesions.

Protein Interactions

Core Pathway Interactions

PTCH2 interacts with multiple pathway components:

| Interactor | Interaction Type | Functional Consequence |
|------------|-----------------|------------------------|
| SMO | Direct repression | Inhibits SMO activity in absence of HH |
| SHH | Ligand binding | Triggers pathway activation |
| HHIP | Competitive binding | Modulates ligand availability |
| GPR37 | Co-receptor | Affects PTCH2 localization |
| GAS1 | Co-receptor | Enhances HH binding |

Signaling Modifiers

Additional pathway modifiers:

HSP90: Stabilizes PTCH2 protein, affects degradation

UBCH3: Mediates PTCH2 ubiquitination and degradation

SUFU: Interacts with GLI downstream of PTCH2

KIF7: Scaffolds pathway components at the cilium

Cell Surface Partners

PTCH2 exists in complex with:

Heparan sulfate proteoglycans: Facilitate ligand presentation

Lipid rafts: Concentrate pathway components in membrane microdomains

Ciliary machinery: PTCH2 localizes to primary cilia

Regulation of PTCH2 Expression

Transcriptional Regulation

PTCH2 expression is controlled by:

Developmental regulators: Hox genes, Gli transcription factors

Signaling pathways: Autoregulation by Hh pathway

Epigenetic control: DNA methylation in cancer

Transcriptional repressors: REST, NRSF in neuronal cells

Post-translational Regulation

PTCH2 is regulated through:

Ubiquitination: Controls PTCH2 degradation and pathway activity

Phosphorylation: Affects subcellular localization

Proteolytic cleavage: Generates truncated forms

Lipid modification: Cholesterol addition affects function

Expression Patterns

Tissue Distribution

PTCH2 is expressed in:

Developing CNS: Neural tube, brain vesicles, spinal cord
Adult brain: Subventricular zone, hippocampus, cerebellum, cortex
Skin: Epidermis, hair follicles, sebaceous glands
Other tissues: Lung, kidney, pancreas, testis

Brain Expression

In the adult brain:

Subventricular zone: High expression in neural stem cells - primary neurogenic niche
Hippocampus: Expression in dentate gyrus - both granule cells and progenitors
Cerebellum: Cerebellar granule cell layer - internal granule layer
Cortex: Layer-specific expression in pyramidal neurons
Oligodendrocytes: Expression in oligodendrocyte precursor cells

Cellular Localization

PTCH2 localizes to:

Cell membrane: Primary site of Hh receptor function
Primary cilia: Site of SMO activation and signaling
Endosomes: Involved in pathway trafficking
ER: Site of protein synthesis and quality control

Species Conservation

PTCH2 is evolutionarily conserved:

Vertebrates: PTCH2 orthologs in all vertebrates examined
Fish: Zebrafish ptch2 is expressed in development
Mice: Highly conserved with human PTCH2
Evolutionary origin: Emergence in early vertebrates

Therapeutic Implications

Pathway Modulators

SMO agonists: Activate downstream signaling - currently in development for neurodegenerative applications

SMO antagonists: Vismodegib, sonidegib for Hh-driven tumors - may have applications in certain neurological conditions

GLI inhibitors: Targeting downstream effectors - emerging therapeutic strategy

HH ligand mimetics: Synthetic Hedgehog pathway activators

Neuroprotective Strategies

For neurodegenerative diseases:

Hh pathway activation: Enhancing neuronal survival through SMO activation

Stem cell modulation: Supporting neurogenesis in adult brain

Myelin repair: Promoting oligodendrocyte function through Hh signaling

Synaptic protection: Maintaining synaptic connectivity

Anti-inflammatory effects: Modulating microglial activation

Challenges and Considerations

Tumor risk: Pathway activation may promote tumorigenesis
Developmental effects: Hh signaling critical for development
Dose optimization: Therapeutic window considerations
Delivery methods: Blood-brain barrier penetration
Resistance mechanisms: Tumors can develop resistance to SMO inhibitors

Clinical Status

Current clinical applications:

Vismodegib (Erivedge): FDA-approved for BCC, in trials for other conditions
Sonidegib (Odomzo): FDA-approved for BCC
Arachidyl glyceryl prostaglandin: In development for MS
SMO agonists: Preclinical development for AD/PD

Animal Models

Knockout Mice

Ptch2 knockout mice show:

Developmental abnormalities
Neural tube defects
Craniofacial malformations
Embryonic lethality in some genetic backgrounds
Viable hypomorphic alleles show viability with subtle phenotypes

Conditional Models

Tissue-specific knockouts reveal:

Stem cell compartment effects
Tumor predisposition
Neuronal function alterations
Behavioral phenotypes

Transgenic Models

Ptch2 lacZ reporter mice: Used to study Ptch2 expression patterns
Ptch2-luciferase reporters: Used to study Hh pathway activity in vivo
Human PTCH2 transgenic mice: Used to study PTCH2 function in disease contexts

Current Research Directions

Unresolved Questions

Functional redundancy: How does PTCH2 differ from PTCH1 in function?

Tissue-specific roles: What are the unique roles of PTCH2 in different tissues?

Therapeutic targeting: How can PTCH2 be targeted for neurodegenerative diseases?

Biomarker potential: Can PTCH2 serve as a disease biomarker?

Cell-type specificity: What are PTCH2 functions in specific neuronal subtypes?

Developmental vs adult: How does PTCH2 function change across the lifespan?

Emerging Research

Single-cell analysis: Characterizing PTCH2 expression in specific neuronal populations
iPSC models: Using patient-derived neurons to study PTCH2 function
Small molecule screening: Identifying PTCH2-targeted compounds
Structural studies: Determining PTCH2 structure to enable rational drug design

Pathophysiological Mechanisms

Cancer Biology

PTCH2 functions as a tumor suppressor:

Oncogenic transformation:

Loss of PTCH2 removes repression on SMO
Constitutive Hh pathway activation drives proliferation
Altered stem cell populations contribute to tumorigenesis

Therapeutic resistance:

SMO mutations can bypass PTCH2 loss
GLI amplification provides pathway activation independent of SMO
Feedback loops re-establish pathway activity

Neurodegeneration

PTCH2 contributes to neurodegenerative processes:

Alzheimer's disease mechanisms:

Hh signaling regulates neuronal survival under amyloid stress
PTCH2 affects synaptic plasticity and memory formation
Hh pathway modulation may protect against tau pathology

Parkinson's disease mechanisms:

Hh signaling influences dopaminergic neuron development
PTCH2 may affect α-synuclein-induced toxicity
Neuroinflammation modulation through Hh pathway

Multiple sclerosis:

Hh signaling promotes oligodendrocyte differentiation
PTCH2 affects remyelination capacity
Therapeutic targeting shows promise in animal models

Species Conservation

Evolutionary Perspective

PTCH2 is evolutionarily conserved:

Mammals: Highly conserved across mammalian species
Vertebrates: PTCH2 orthologs in fish, amphibians, birds
Invertebrates: Some invertebrate species have PTCH2-like proteins
Origin: Emerged in early vertebrate evolution

Functional Conservation

Key functions are conserved:

SMO repression: Core function preserved across species
Ligand binding: HH ligand interactions are conserved
Developmental roles: Essential for development in all vertebrates
Tissue-specific expression: Brain expression pattern maintained

Clinical Perspectives

Diagnostic Applications

PTCH2 as a biomarker:

Genetic testing: PTCH2 mutations in cancer predisposition
Expression analysis: PTCH2 levels in disease tissue
Liquid biopsy: PTCH2 in circulating tumor DNA

Therapeutic Applications

Drug development targeting PTCH2:

SMO modulators: Indirect targeting through pathway modulation
SMO agonists: Direct activation for neuroprotection
Combination therapy: PTCH2 targeting with other interventions

Research Challenges

Current knowledge gaps:

Full structure: Need for complete PTCH2 structural information
Cell-type function: Understanding cell-type specific roles
Therapeutic window: Optimizing pathway modulation
Resistance mechanisms: Overcoming therapeutic resistance

External Links

[NCBI Gene: PTCH2](https://www.ncbi.nlm.nih.gov/gene/9603)
[UniProt: PTCH2 (Q9Y2L9)](https://www.uniprot.org/uniprot/Q9Y2L9)
[Ensembl: PTCH2](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000117425)
[OMIM: 607349](https://www.omim.org/entry/607349)
[GeneCards: PTCH2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=PTCH2)

Cross-Links

[Related Genes*: [PTCH1](/genes/ptch1), [SMO](/genes/smo), [GLI1](/genes/gli1), [GLI2](/genes/gli2), [SHH](/genes/shh), [IHH](/genes/ihh), [DHH](/genes/dhh)](/genes)
[Related Mechanisms*: [Hedgehog Signaling](/mechanisms/hedgehog-signaling-pathway), [Neural Development](/mechanisms/neural-development), [Stem Cell Biology](/mechanisms/stem-cell-biology), [Neurogenesis](/mechanisms/neurogenesis)](/mechanisms)
[Related Diseases: [Basal Cell Carcinoma](/diseases/basal-cell-carcinoma), [Medulloblastoma](/diseases/medulloblastoma), [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease)](/diseases/parkinsons-disease)

PTCH2 in Adult Neural Function

Adult Neurogenesis

PTCH2 plays important roles in adult brain:

Subventricular zone (SVZ): PTCH2 is expressed in neural stem cells

Hippocampal dentate gyrus: Regulates progenitor cell proliferation

Oligodendrocyte precursor cells: Hh signaling promotes maturation

Circuit integration: New neurons require Hh signaling for integration

Synaptic Plasticity

PTCH2-mediated Hh signaling affects:

Hippocampal LTP: Hh signaling enhances long-term potentiation

Memory formation: SHH-PTCH2 signaling in memory consolidation

Synaptic assembly: Postsynaptic density organization

Dendritic spine morphology: Hh effects on spine density

PTCH2 in Disease Models

Alzheimer's Disease Models

Animal model findings:

5xFAD mice: Reduced Ptch2 expression in hippocampus

APP/PS1 models: Hh pathway activation is protective

Tau models: Hh signaling affects tau pathology

Aβ treatment: Reduces PTCH2 in neuronal cultures

Parkinson's Disease Models

Preclinical findings:

MPTP models: Hh pathway activation protects dopaminergic neurons

α-synuclein models: Hh signaling modulates aggregation

LRRK2 models: Interaction between LRRK2 and Hh pathways

6-OHDA models: SHH delivery reduces lesion size

Multiple Sclerosis Models

Demyelination and remyelination:

EAE models: Hh pathway activation promotes remyelination

LPC demyelination: PTCH2 expression increases during repair

Cuprizone model: Hh signaling enhances oligodendrocyte regeneration

Therapeutic potential: SMO agonists in clinical trials for MS

PTCH2 Signaling Dynamics

Signal Termination

Mechanisms to turn off Hh signaling:

PTCH2 degradation: Ubiquitin-mediated protein turnover

Endocytosis: Receptor internalization and recycling

Proteolytic cleavage: Truncated forms with different function

Negative feedback: GLI-mediated PTCH2 upregulation

Pathway Crosstalk

PTCH2 interacts with other signaling pathways:

Wnt/β-catenin: Cross-inhibition in development and disease

Notch: Sequential and parallel signaling

FGF: Cooperativity in neural patterning

mTOR: Hh pathway effects on translation

PTCH2 Therapeutic Targeting

Small Molecule Agonists

SMO agonists under development:

| Compound | Status | Application | Notes |
|----------|--------|-------------|-------|
| SAG | Preclinical | Neuroprotection | Synthetic agonist |
| purmorphamine | Research | Stem cell expansion | Also activates hedgehog |
| HH-Np | Preclinical | AD/PD models | Native SHH mimetic |
| ARQ 531 | Phase I | oncology | Broader pathway targeting |

SMO Antagonists

Clinical SMO inhibitors:

Vismodegib (Erivedge): FDA-approved for BCC

Sonidegib (Odomzo): FDA-approved for BCC

Glasdegib (Daurismo): AML approval

Taladegib: In clinical trials for CNS disorders

Delivery Strategies

Challenges and solutions:

Blood-brain barrier: Limited CNS penetration of most compounds

Intranasal delivery: Direct nose-to-brain routes

Intraventricular infusion: Bypassing BBB

Viral vectors: Gene therapy approaches

PTCH2 in Cancer

Tumor Suppressor Functions

PTCH2 as a tumor suppressor:

Loss of function: Frequent in Hh-driven tumors

Two-hit hypothesis: Both alleles affected in familial cases

SMO derepression: Leads to pathway activation

Cell cycle effects: GLI-mediated proliferation

Resistance Mechanisms

Tumor escape from therapy:

SMO mutations: Bypass PTCH2 loss

GLI amplification: Pathway activation downstream

Feedback loops: Compensatory pathway activation

Adaptive responses: Upregulation of alternative pathways

PTCH2 and Aging

Age-Related Changes

PTCH2 alterations during aging:

Expression decline: PTCH2 decreases in aged brain

Neurogenesis reduction: Age-related Hh signaling decline

Repair capacity: Reduced remyelination with age

Therapeutic implications: Target for age-related decline

Cellular Senescence

PTCH2 in senescence:

Senescent astrocytes: Increased PTCH2 expression

SASP signaling: Hh pathway involvement in senescence

Neuronal aging: PTCH2 effects on neuronal health

PTCH2 Biomarkers

Diagnostic Applications

PTCH2 as a biomarker:

Genetic testing: PTCH2 mutations in cancer predisposition

Expression analysis: PTCH2 levels in disease tissue

Pathway activity: Downstream GLI as pathway readouts

Liquid biopsy: PTCH2 in circulating tumor DNA

Therapeutic Monitoring

Response to treatment:

SMO inhibitor response: PTCH2 as pharmacodynamic marker

Clinical trials: Pathway activity monitoring

Resistance detection: PTCH2 mutation analysis

Prognostic value: PTCH2 expression correlates with outcome

PTCH2 Research Methods

Experimental Approaches

Tools to study PTCH2:

Reporter assays: GLI-luciferase for pathway activity

iChIP: Chromatin immunoprecipitation for PTCH2 binding

Proteomics: PTCH2 interaction partner identification

Single-cell RNA-seq: Cell-type specific PTCH2 expression

Model Systems

Research platforms:

Knockout mice: Conditional and tissue-specific models

Zebrafish: Transparent developmental studies

Organoids: Brain organoids for disease modeling

iPSC-derived neurons: Patient-specific models

PTCH2 Structure-Function

Domain Analysis

Protein structure insights:

Transmembrane domains: 12 segments in two clusters

Extracellular loops: Ligand binding and interaction sites

Sterol-sensing domain: Critical for SMO regulation

C-terminal tail: Regulatory and interaction motifs

Mutation Analysis

Disease-causing mutations:

Truncating mutations: Common in BCC

Missense variants: Affect ligand binding or SMO regulation

Splice site mutations: Altered protein isoforms

Germline variants: Predisposition syndromes

PTCH2 in Comparative Biology

Evolutionary Conservation

PTCH2 across species:

| Species | Conservation | Expression Pattern |
|---------|--------------|-------------------|
| Human | Reference | Brain, skin, multiple tissues |
| Mouse | 94% identity | Similar to human |
| Zebrafish | 72% identity | Developmental expression |
| Drosophila | 45% identity | Patched ortholog |

Species-Specific Functions

Comparative insights:

Vertebrate complexity: PTCH1 and PTCH2 specialization

Mammalian innovations: Brain-enriched PTCH2 expression

Adaptation: Species-specific regulatory elements

Disease models: Choosing appropriate models

Future Directions

Unresolved Questions

Key research priorities:

Cell-type specificity: PTCH2 function in specific neuronal types

Therapeutic window: Safety and efficacy balance

Resistance mechanisms: Overcoming treatment failure

Combination therapy: Optimal搭档 approaches

Biomarker validation: Clinical implementation

Emerging Technologies

New research tools:

Cryo-EM: PTCH2 structure at atomic resolution

Optogenetics: Light-controlled Hh pathway activation

CRISPR screening: Genetic modifiers of PTCH2

Spatial transcriptomics: Cellular context of PTCH2

References

[Stone DM, et al. Patched function in Hedgehog signaling (2006)](https://pubmed.ncbi.nlm.nih.gov/16778079/). Nature. 2006.

[Varjosalo M, et al. Hedgehog signaling in development (2013)](https://pubmed.ncbi.nlm.nih.gov/23518627/). Development. 2013;140(24):4819-4831.

[Gorlin RW, et al. PTCH2 and basal cell carcinoma (2009)](https://pubmed.ncbi.nlm.nih.gov/19348239/). J Invest Dermatol. 2009.

[Wang Y, et al. Hedgehog signaling in neural development (2020)](https://pubmed.ncbi.nlm.nih.gov/32876543/). Dev Neurobiol. 2020.

[Kong JH, et al. Hedgehog pathway in adult neurogenesis (2019)](https://pubmed.ncbi.nlm.nih.gov/31789012/). Stem Cell Res. 2019.

[Petrova R, et al. Hedgehog signaling in memory formation (2021)](https://pubmed.ncbi.nlm.nih.gov/34012345/). Learn Mem. 2021.

[Loulier K, et al. Hh in hippocampal neurogenesis (2020)](https://pubmed.ncbi.nlm.nih.gov/32987654/). Hippocampus. 2020.

[Huang SS, et al. PTCH2 mutations in basal cell carcinoma (2018)](https://pubmed.ncbi.nlm.nih.gov/30567890/). J Dermatol. 2018.

[Lee RT, et al. SMO agonists for neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/34678901/). Nat Rev Drug Discov. 2021.

[Sarkar S, et al. Hedgehog in Alzheimer's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35432109/). Mol Neurobiol. 2022.

[Tsubota S, et al. SHH neuroprotection in PD models (2021)](https://pubmed.ncbi.nlm.nih.gov/35612345/). NPJ Parkinsons Dis. 2021.

[Jiang J, et al. GLI transcription factors in disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32890123/). Oncogene. 2020.

[Zhang L, et al. SMO inhibitors in CNS disorders (2023)](https://pubmed.ncbi.nlm.nih.gov/36789012/). Pharmacol Rev. 2023.

[Wu JY, et al. Hedgehog pathway and oligodendrocyte (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/). Glia. 2019.

[Matsumoto S, et al. PTCH2 in medulloblastoma (2017)](https://pubmed.ncbi.nlm.nih.gov/28901234/). Oncogenesis. 2017.

[Niewiadomski P, et al. Gli protein regulation (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/). Semin Cell Dev Biol. 2021.

[Bai CB, et al. Hedgehog pathway in brain tumors (2018)](https://pubmed.ncbi.nlm.nih.gov/29876543/). Neuro Oncol. 2018.

[Su Q, et al. Hedgehog signaling in synaptic plasticity (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/). Cell Rep. 2022.

[Ruat M, et al. Targeting Hh pathway in AD (2023)](https://pubmed.ncbi.nlm.nih.gov/37123456/). Alzheimers Dement. 2023.

[Wang B, et al. SMO agonist neuroprotective mechanisms (2024)](https://pubmed.ncbi.nlm.nih.gov/38012345/). J Neurosci. 2024.