Details for: NETO2

Gene ID: 81831

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: NETO2

Ensembl ID: ENSG00000171208

Description: neuropilin and tolloid like 2

Cell Significance Landscape

Associated with

  • Glutamatergic synapse
    (GO:0098978)
  • Ionotropic glutamate receptor binding
    (GO:0035255)
  • Neurotransmitter receptor localization to postsynaptic specialization membrane
    (GO:0099645)
  • Postsynaptic density
    (GO:0014069)
  • Postsynaptic density membrane
    (GO:0098839)
  • Protein binding
    (GO:0005515)
  • Regulation of neurotransmitter receptor localization to postsynaptic specialization membrane
    (GO:0098696)

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • sst GABAergic cortical interneuron CL4023017
    CSI 34.36
    rCSI 44.3%
    PRS 83.54
  • VIP GABAergic cortical interneuron CL4023016
    CSI 30.42
    rCSI 36.34%
    PRS 82.52
  • sncg GABAergic cortical interneuron CL4023015
    CSI 24.73
    rCSI 39.77%
    PRS 83.48
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 19.21
    rCSI 23.9%
    PRS 80.35
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 17.51
    rCSI 30.92%
    PRS 81.83
  • interneuron CL0000099
    CSI 14.31
    rCSI 28.74%
    PRS 88.09
  • epithelial cell CL0000066
    CSI 14.11
    rCSI 21.68%
    PRS 82.15
  • progenitor cell CL0011026
    CSI 12.87
    rCSI 27.37%
    PRS 87.28
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 11.89
    rCSI 37.19%
    PRS 85.3
  • neural crest cell CL0011012
    CSI 11.77
    rCSI 9.3%
    PRS 87.39
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 11.52
    rCSI 43.55%
    PRS 82.64
  • amacrine cell CL0000561
    CSI 10.98
    rCSI 31.83%
    PRS 85.96
  • L6b glutamatergic cortical neuron CL4023038
    CSI 10.93
    rCSI 34.14%
    PRS 83.56
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 9.37
    rCSI 22.78%
    PRS 80.36
  • neuroblast (sensu Nematoda and Protostomia) CL0000338
    CSI 8.38
    rCSI 9.67%
    PRS 86.41
  • radial glial cell CL0000681
    CSI 8.31
    rCSI 11.55%
    PRS 91.45
  • choroid plexus epithelial cell CL0000706
    CSI 8.28
    rCSI 13.56%
    PRS 87.25
  • retinal pigment epithelial cell CL0002586
    CSI 8.1
    rCSI 16.08%
    PRS 90.15
  • inhibitory interneuron CL0000498
    CSI 7.96
    rCSI 18.37%
    PRS 85.59
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 7.94
    rCSI 13.33%
    PRS 82.52
  • neuroblast (sensu Vertebrata) CL0000031
    CSI 7.63
    rCSI 9.79%
    PRS 89.83
  • GABAergic amacrine cell CL4030027
    CSI 7.51
    rCSI 25.71%
    PRS 82.14
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 7.35
    rCSI 26.45%
    PRS 80.63
  • glioblast CL0000030
    CSI 7.2
    rCSI 11.48%
    PRS 86.61
  • Mueller cell CL0000636
    CSI 7
    rCSI 15.97%
    PRS 87.6
  • cerebral cortex GABAergic interneuron CL0010011
    CSI 6.42
    rCSI 18.94%
    PRS 92.66
  • elicited macrophage CL0000861
    CSI 6.12
    rCSI 5.62%
    PRS 96.37
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 6.03
    rCSI 35.53%
    PRS 82.83
  • medium spiny neuron CL1001474
    CSI 6.02
    rCSI 51.86%
    PRS 86.39
  • neuron CL0000540
    CSI 6
    rCSI 15.97%
    PRS 82.69
  • blood vessel endothelial cell CL0000071
    CSI 5.7
    rCSI 11.82%
    PRS 91.64
  • basal cell CL0000646
    CSI 5.68
    rCSI 7.59%
    PRS 90.54
  • stem cell CL0000034
    CSI 5.39
    rCSI 5.2%
    PRS 89.82
  • GABAergic neuron CL0000617
    CSI 5.17
    rCSI 17.32%
    PRS 81.65
  • central nervous system neuron CL2000029
    CSI 5.11
    rCSI 37.53%
    PRS 86.41
  • colon epithelial cell CL0011108
    CSI 4.86
    rCSI 5.09%
    PRS 90.94
  • neural cell CL0002319
    CSI 4.24
    rCSI 16%
    PRS 80.75
  • cerebellar granule cell CL0001031
    CSI 3.84
    rCSI 5.65%
    PRS 88.97
  • Kupffer cell CL0000091
    CSI 3.26
    rCSI 7.46%
    PRS 93.78
  • intermediate monocyte CL0002393
    CSI 3.12
    rCSI 4.71%
    PRS 96.06
  • differentiation-committed oligodendrocyte precursor CL4023059
    CSI 3.09
    rCSI 5.62%
    PRS 87.76
  • glutamatergic neuron CL0000679
    CSI 2.89
    rCSI 5.95%
    PRS 82.98
  • dopaminergic neuron CL0000700
    CSI 2.89
    rCSI 16.33%
    PRS 84.03
  • serotonergic neuron CL0000850
    CSI 2.69
    rCSI 12.02%
    PRS 80.5
  • GABAergic interneuron CL0011005
    CSI 2.65
    rCSI 41.81%
    PRS 93.5
  • CD14-positive monocyte CL0001054
    CSI 2.35
    rCSI 2.93%
    PRS 97.03
  • L2/3 intratelencephalic projecting glutamatergic neuron CL4030059
    CSI 2.3
    rCSI 4.99%
    PRS 83.52
  • direct pathway medium spiny neuron CL4023026
    CSI 1.87
    rCSI 44.84%
    PRS 80.23
  • indirect pathway medium spiny neuron CL4023029
    CSI 1.85
    rCSI 44.69%
    PRS 80.32
  • cerebellar neuron CL1001611
    CSI 1.83
    rCSI 16.07%
    PRS 82.48
  • L5/6 near-projecting glutamatergic neuron CL4030067
    CSI 1.8
    rCSI 5.93%
    PRS 83.33
  • midbrain dopaminergic neuron CL2000097
    CSI 1.62
    rCSI 10.41%
    PRS 87.59
  • L4 intratelencephalic projecting glutamatergic neuron CL4030063
    CSI 1.56
    rCSI 3.72%
    PRS 84.51
  • retinal ganglion cell CL0000740
    CSI 1.43
    rCSI 3.17%
    PRS 84.32
  • cerebral cortex pyramidal neuron CL4023111
    CSI 1.08
    rCSI 6.65%
    PRS 93.19
  • neural progenitor cell CL0011020
    CSI 1.08
    rCSI 4.74%
    PRS 83.58
  • glial cell CL0000125
    CSI 0.81
    rCSI 3.07%
    PRS 87.58

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

Loading network (please wait)...

Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [NETO2](/details-gene/81831), or Neuropilin And Tolloid Like 2, is a protein-coding gene that functions as an auxiliary subunit for kainate-type ionotropic glutamate receptors. Its primary role is to modulate the function and localization of these receptors at the synapse. Functional annotations strongly link [NETO2](/details-gene/81831) to the molecular machinery of the postsynaptic density, particularly within [glutamatergic synapses](/details-cell/GO:0098978). Expression data reveals a highly specific enrichment within the central nervous system, where it serves as a significant marker for various subtypes of cortical [interneurons](/details-cell/CL0000099), including [sst GABAergic cortical interneurons](/details-cell/CL4023017) and [VIP GABAergic cortical interneurons](/details-cell/CL4023016), suggesting a critical role in regulating cortical inhibitory circuits. ## Cellular Roles and Expression Landscape The expression profile of [NETO2](/details-gene/81831) indicates a highly specialized function within the nervous system. **Overall**, the gene shows its most significant expression in a diverse array of neuronal subtypes, particularly inhibitory GABAergic [interneurons](/details-cell/CL0000099) of the cortex. It is a top marker for [sst GABAergic cortical interneurons](/details-cell/CL4023017) (CSI: 34.36), [VIP GABAergic cortical interneurons](/details-cell/CL4023016) (CSI: 30.42), [sncg GABAergic cortical interneurons](/details-cell/CL4023015) (CSI: 24.73), and [pvalb GABAergic cortical interneurons](/details-cell/CL4023018) (CSI: 19.21). This strong and specific expression pattern across functionally distinct classes of [interneurons](/details-cell/CL0000099) suggests that [NETO2](/details-gene/81831) is a key molecular component defining the synaptic properties of these cells and is crucial for maintaining the excitatory-inhibitory balance within cortical microcircuits. Beyond its prominent role in cortical [interneurons](/details-cell/CL0000099), [NETO2](/details-gene/81831) is also significantly expressed in other neuronal populations, including [near-projecting glutamatergic cortical neurons](/details-cell/CL4023012), [L6b glutamatergic cortical neurons](/details-cell/CL4023038), and retinal [amacrine cells](/details-cell/CL0000561). Moderate significance is also noted in [epithelial cells](/details-cell/CL0000066) and various neural [progenitor cells](/details-cell/CL0011026), which may point to roles in development or non-canonical functions outside of classic neurotransmission. ## Pathways and Molecular Function The functional annotations for [NETO2](/details-gene/81831) align precisely with its observed expression in neuronal cells. At the molecular level, it is known for its direct interaction with glutamate receptors, as highlighted by its annotation for [ionotropic glutamate receptor binding](/details-cell/GO:0035255). This interaction is central to its biological process of regulating the [localization of neurotransmitter receptors to the postsynaptic specialization membrane](/details-cell/GO:0099645). Consistent with these roles, [NETO2](/details-gene/81831) is a resident protein of key synaptic structures. It is an integral component of the [postsynaptic density](/details-cell/GO:0014069) and the [glutamatergic synapse](/details-cell/GO:0098978) itself. This localization positions it to directly influence synaptic strength and plasticity by controlling the number and properties of kainate receptors available at the postsynaptic membrane of the neurons where it is highly expressed. ## Research Directions The specific enrichment of [NETO2](/details-gene/81831) in distinct subtypes of cortical [interneurons](/details-cell/CL0000099) raises important questions about its role in defining the functional diversity of these critical cells. **Proposed Hypotheses:** 1. [NETO2](/details-gene/81831) expression levels and/or splice variants differ across GABAergic [interneuron](/details-cell/CL0000099) subtypes (e.g., SST+, VIP+, PVALB+), leading to differential trafficking and kinetic properties of kainate receptors, thereby contributing to the unique electrophysiological fingerprints of these cell types. 2. The interaction of [NETO2](/details-gene/81831) with kainate receptors is dynamically regulated by neuronal activity, serving as a molecular mechanism for homeostatic synaptic scaling in cortical inhibitory circuits. 3. In [epithelial cells](/details-cell/CL0000066), [NETO2](/details-gene/81831) engages with alternative binding partners or receptor types, mediating functions unrelated to neurotransmission, such as cell adhesion or barrier integrity. **Experimental Approach:** To test the first hypothesis, a combination of molecular and electrophysiological studies could be employed. One could use subtype-specific Cre-driver mouse lines (e.g., Sst-Cre, Pvalb-Cre) to introduce a conditional knockout of *Neto2*. Subsequent whole-cell patch-clamp recordings from the targeted [interneuron](/details-cell/CL0000099) populations in acute cortical slices would allow for a direct comparison of kainate receptor-mediated currents (e.g., amplitude, decay kinetics, and pharmacology). Concurrently, super-resolution microscopy on these same genetically-defined cells could quantify any changes in the synaptic clustering and density of kainate receptor subunits. **Therapeutic Potential:** Given that imbalances in cortical excitation and inhibition are implicated in neurological and psychiatric disorders such as epilepsy and schizophrenia, [NETO2](/details-gene/81831) presents a potential therapeutic target. Its high specificity for neuronal populations, particularly [interneurons](/details-cell/CL0000099), suggests that targeting it could offer a more refined approach than modulating glutamate receptors directly, which are expressed ubiquitously. Small molecules designed to either enhance or disrupt the [NETO2](/details-gene/81831)-kainate receptor interaction could be developed. The therapeutic strategy would be context-dependent: inhibition of its function could reduce hyperexcitability, whereas activation or enhancement might restore function in circuits characterized by inhibitory deficits.

Genular Protein ID: 4252154992

Symbol: NETO2_HUMAN

Name: Neuropilin and tolloid-like protein 2

UniProtKB Accession Codes:

Q8NC67 J3KNF1 Q7Z381 Q8ND51 Q96SP4 Q9NVY8

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 2 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 11 Ensembl 2 ExpressionAtlas 1 GO 6 Gene3D 2 GeneCards 1 GeneTree 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 3 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 RefSeq 2 SIGNOR 1 SMART 2 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TCDB 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 12975309

Title: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.

PubMed ID: 12975309

DOI: 10.1101/gr.1293003

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 17974005

Title: The full-ORF clone resource of the German cDNA consortium.

PubMed ID: 17974005

DOI: 10.1186/1471-2164-8-399

PubMed ID: 15616553

Title: The sequence and analysis of duplication-rich human chromosome 16.

PubMed ID: 15616553

DOI: 10.1038/nature03187

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 15340161

Title: Signal peptide prediction based on analysis of experimentally verified cleavage sites.

PubMed ID: 15340161

DOI: 10.1110/ps.04682504

Sequence Information:

  • Length: 525
  • Mass: 59393
  • Checksum: EA6F98C3A88220EA
  • Sequence:
    • MALERLCSVL KVLLITVLVV EGIAVAQKTQ DGQNIGIKHI PATQCGIWVR TSNGGHFASP 
NYPDSYPPNK ECIYILEAAP RQRIELTFDE HYYIEPSFEC RFDHLEVRDG PFGFSPLIDR 
YCGVKSPPLI RSTGRFMWIK FSSDEELEGL GFRAKYSFIP DPDFTYLGGI LNPIPDCQFE 
LSGADGIVRS SQVEQEEKTK PGQAVDCIWT IKATPKAKIY LRFLDYQMEH SNECKRNFVA 
VYDGSSSIEN LKAKFCSTVA NDVMLKTGIG VIRMWADEGS RLSRFRMLFT SFVEPPCTSS 
TFFCHSNMCI NNSLVCNGVQ NCAYPWDENH CKEKKKAGVF EQITKTHGTI IGITSGIVLV 
LLIISILVQV KQPRKKVMAC KTAFNKTGFQ EVFDPPHYEL FSLRDKEISA DLADLSEELD 
NYQKMRRSST ASRCIHDHHC GSQASSVKQS RTNLSSMELP FRNDFAQPQP MKTFNSTFKK 
SSYTFKQGHE CPEQALEDRV MEEIPCEIYV RGREDSAQAS ISIDF

Genular Protein ID: 2110276903

Symbol: Q32NC3_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q32NC3

Database IDs:

ARBA 1 AlphaFoldDB 1 BioGRID-ORCS 1 CDD 2 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 2 GO 2 Gene3D 2 InterPro 6 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PROSITE 4 PROSITE-ProRule 2 PeptideAtlas 1 Pfam 2 RefSeq 1 SAM 1 SMART 2 SUPFAM 2

Citations:

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

Sequence Information:

  • Length: 329
  • Mass: 37324
  • Checksum: A7D298CEE16B5315
  • Sequence:
    • MALERLCSVL KVLLITVLVV EGIAVAQKTQ DGQNIGIKHI PATQCGIWVR TSNGGHFASP 
NYPDSYPPNK ECIYILEAAP RQRIELTFDE HYYIEPSFEC RFDHLEVRDG PFGFSPLIDR 
YCGVKSPPLI RSTGRFMWIK FSSDEELEGL GFRAKYSFIP DPDFTYLGDC QFELSGADGI 
VRSSQVEQEE KTKPGQAVDC IWTIKATPKA KIYLRFLDYQ MEHSNECKRN FVAVYDGSSS 
IENLKAKFCS TVANDVMLKT GIGVIRMWAD EGSRLSRFRM LFTSFVEPPC TSSTFFCHSN 
MCINNSLVCN GVQNCAYPWD ENHCKKKKK