Details for: CUX2

Gene ID: 23316

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: CUX2

Ensembl ID: ENSG00000111249

Description: cut like homeobox 2

Cell Significance Landscape

Associated with

  • Chromatin
    (GO:0000785)
  • Cognition
    (GO:0050890)
  • Dna-binding transcription factor activity, rna polymerase ii-specific
    (GO:0000981)
  • Dna-binding transcription repressor activity, rna polymerase ii-specific
    (GO:0001227)
  • Extracellular exosome
    (GO:0070062)
  • Negative regulation of transcription by rna polymerase ii
    (GO:0000122)
  • Nucleus
    (GO:0005634)
  • Positive regulation of dendrite morphogenesis
    (GO:0050775)
  • Positive regulation of dendritic spine morphogenesis
    (GO:0061003)
  • Positive regulation of excitatory postsynaptic potential
    (GO:2000463)
  • Positive regulation of gene expression
    (GO:0010628)
  • Positive regulation of synapse assembly
    (GO:0051965)
  • Regulation of transcription by rna polymerase ii
    (GO:0006357)
  • Rna polymerase ii cis-regulatory region sequence-specific dna binding
    (GO:0000978)
  • Rna polymerase ii transcription regulatory region sequence-specific dna binding
    (GO:0000977)
  • Sequence-specific dna binding
    (GO:0043565)
  • Sequence-specific double-stranded dna binding
    (GO:1990837)
  • Short-term memory
    (GO:0007614)

Significant Cells

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

  • pvalb GABAergic cortical interneuron CL4023018
    CSI 32.91
    rCSI 40.94%
    PRS 61.88
  • choroid plexus epithelial cell CL0000706
    CSI 30.43
    rCSI 49.83%
    PRS 71.25
  • sst GABAergic cortical interneuron CL4023017
    CSI 24.47
    rCSI 31.54%
    PRS 65.19
  • L2/3 intratelencephalic projecting glutamatergic neuron CL4030059
    CSI 23.68
    rCSI 51.36%
    PRS 69.34
  • hepatocyte CL0000182
    CSI 23.26
    rCSI 41.64%
    PRS 80.75
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 20.2
    rCSI 49.1%
    PRS 62.01
  • radial glial cell CL0000681
    CSI 18.85
    rCSI 26.19%
    PRS 79.86
  • neuroblast (sensu Nematoda and Protostomia) CL0000338
    CSI 14.95
    rCSI 17.26%
    PRS 73.73
  • interneuron CL0000099
    CSI 14.33
    rCSI 28.78%
    PRS 72.22
  • glioblast CL0000030
    CSI 14.33
    rCSI 22.86%
    PRS 73.14
  • GABAergic amacrine cell CL4030027
    CSI 12.99
    rCSI 44.5%
    PRS 67.81
  • neural crest cell CL0011012
    CSI 12.18
    rCSI 9.63%
    PRS 70.83
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 11.17
    rCSI 34.94%
    PRS 68.02
  • progenitor cell CL0011026
    CSI 9.72
    rCSI 20.67%
    PRS 75.74
  • retinal bipolar neuron CL0000748
    CSI 9.6
    rCSI 17.97%
    PRS 70.17
  • H2 horizontal cell CL0004218
    CSI 9.51
    rCSI 47.27%
    PRS 76.29
  • inhibitory interneuron CL0000498
    CSI 8.82
    rCSI 20.36%
    PRS 69.8
  • rod bipolar cell CL0000751
    CSI 8.54
    rCSI 15.34%
    PRS 74.99
  • cerebral cortex GABAergic interneuron CL0010011
    CSI 8.53
    rCSI 25.18%
    PRS 82.38
  • neural cell CL0002319
    CSI 8.42
    rCSI 31.77%
    PRS 64.95
  • neuroblast (sensu Vertebrata) CL0000031
    CSI 8.4
    rCSI 10.79%
    PRS 77.64
  • glutamatergic neuron CL0000679
    CSI 7.75
    rCSI 15.93%
    PRS 68.95
  • periportal region hepatocyte CL0019026
    CSI 7.49
    rCSI 29.12%
    PRS 80.69
  • H1 horizontal cell CL0004217
    CSI 7.14
    rCSI 28.27%
    PRS 76.65
  • hepatic stellate cell CL0000632
    CSI 6.93
    rCSI 25.96%
    PRS 74.28
  • glycinergic amacrine cell CL4030028
    CSI 6.89
    rCSI 17.95%
    PRS 76.12
  • cerebral cortex neuron CL0010012
    CSI 6.47
    rCSI 26.37%
    PRS 73.57
  • medial ganglionic eminence derived interneuron CL4023063
    CSI 6.46
    rCSI 64.54%
    PRS 39.08
  • centrilobular region hepatocyte CL0019029
    CSI 6.33
    rCSI 16.51%
    PRS 79.87
  • amacrine cell CL0000561
    CSI 6.14
    rCSI 17.8%
    PRS 71.26
  • ependymal cell CL0000065
    CSI 5.85
    rCSI 11.87%
    PRS 60.38
  • central nervous system neuron CL2000029
    CSI 4.92
    rCSI 36.17%
    PRS 69.27
  • retinal ganglion cell CL0000740
    CSI 4.7
    rCSI 10.39%
    PRS 67.65
  • Kupffer cell CL0000091
    CSI 4.62
    rCSI 10.57%
    PRS 82.29
  • serotonergic neuron CL0000850
    CSI 4.51
    rCSI 20.16%
    PRS 65.67
  • L4 intratelencephalic projecting glutamatergic neuron CL4030063
    CSI 4.43
    rCSI 10.61%
    PRS 68.48
  • midzonal region hepatocyte CL0019028
    CSI 4.29
    rCSI 10.07%
    PRS 81.26
  • cerebral cortex endothelial cell CL1001602
    CSI 4.29
    rCSI 7.41%
    PRS 73.38
  • dopaminergic neuron CL0000700
    CSI 4.21
    rCSI 23.77%
    PRS 67.89
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 4.19
    rCSI 7.03%
    PRS 64
  • GABAergic neuron CL0000617
    CSI 4
    rCSI 13.4%
    PRS 65.62
  • glial cell CL0000125
    CSI 3.9
    rCSI 14.86%
    PRS 72.84
  • cardiac muscle cell CL0000746
    CSI 3.78
    rCSI 5.42%
    PRS 71.51
  • basket cell CL0000118
    CSI 3.38
    rCSI 21.15%
    PRS 61.66
  • retina horizontal cell CL0000745
    CSI 3
    rCSI 4.57%
    PRS 78.39
  • ON parasol ganglion cell CL4033052
    CSI 2.38
    rCSI 33.74%
    PRS 72.84
  • starburst amacrine cell CL0004232
    CSI 1.86
    rCSI 15.67%
    PRS 69.35
  • intrahepatic cholangiocyte CL0002538
    CSI 1.61
    rCSI 3.86%
    PRS 84.71
  • midbrain dopaminergic neuron CL2000097
    CSI 1.61
    rCSI 10.29%
    PRS 77.38
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 1.54
    rCSI 2.72%
    PRS 63.46
  • neural progenitor cell CL0011020
    CSI 1.49
    rCSI 6.57%
    PRS 70.03
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 0.86
    rCSI 3.08%
    PRS 61.97
  • ON midget ganglion cell CL4033046
    CSI 0.84
    rCSI 17.09%
    PRS 71.45
  • OFF midget ganglion cell CL4033047
    CSI 0.82
    rCSI 16.69%
    PRS 72.55
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 0.77
    rCSI 2.92%
    PRS 64.6

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 [CUX2](/details-gene/23316) (Cut Like Homeobox 2) is a protein-coding gene that encodes a member of the homeobox family of DNA-binding transcription factors. This protein plays a crucial role in regulating gene expression by binding to specific DNA sequences, acting as both a transcriptional repressor and activator. **Overall**, expression data reveals that [CUX2](/details-gene/23316) is a highly significant marker for specific neuronal populations, particularly [pvalb GABAergic cortical interneurons](/details-cell/CL4023018) and other glutamatergic and GABAergic neurons within the cerebral cortex. Its function is essential for proper neuronal development, including dendrite and synapse formation, which are fundamental to cognitive processes. Consistent with its role in the nervous system, recurrent de novo variants in [CUX2](/details-gene/23316) have been clinically associated with a spectrum of neurodevelopmental disorders, including intellectual disability, epilepsy, and autism ([Link](https://doi.org/10.1002/ana.25222), [Link](https://doi.org/10.1038/s41431-018-0184-5)). ## Cellular Roles and Expression Landscape The expression profile of [CUX2](/details-gene/23316) highlights its specialized role in the central nervous system, with additional significant expression in select non-neuronal tissues. **Overall**, the gene shows its highest significance in distinct neuronal subtypes. It is a defining marker for [pvalb GABAergic cortical interneurons](/details-cell/CL4023018) (CSI: 32.91) and [sst GABAergic cortical interneurons](/details-cell/CL4023017) (CSI: 24.47), suggesting a critical function in establishing the identity and function of these inhibitory circuits. High significance is also observed in excitatory neurons, such as [L2/3 intratelencephalic projecting glutamatergic neurons](/details-cell/CL4030059) (CSI: 23.68), indicating a broader role in cortical development and connectivity. Its expression in progenitor cells like [radial glial cells](/details-cell/CL0000681) (CSI: 18.85) and [neuroblasts](/details-cell/CL0000338) (CSI: 14.95) is consistent with a role in neurogenesis and neuronal differentiation. Interestingly, [CUX2](/details-gene/23316) also demonstrates high significance in non-neuronal cell types, including [choroid plexus epithelial cells](/details-cell/CL0000706) (CSI: 30.43) and [hepatocytes](/details-cell/CL0000182) (CSI: 23.26). This suggests that [CUX2](/details-gene/23316) may have distinct, tissue-specific regulatory functions outside of the nervous system, potentially related to secretion in the choroid plexus or metabolic regulation in the liver. ## Pathways and Molecular Function Functionally, [CUX2](/details-gene/23316) is a [DNA-binding transcription factor activity, rna polymerase ii-specific](/details-go/GO:0000981) that localizes to the [nucleus](/details-go/GO:0005634) and interacts with [chromatin](/details-go/GO:0000785). It exhibits dual regulatory capacity, capable of both [negative regulation of transcription by rna polymerase ii](/details-go/GO:0000122) and [positive regulation of gene expression](/details-go/GO:0010628). This transcriptional activity directly supports its biological roles in neurodevelopment. [CUX2](/details-gene/23316) is implicated in processes critical for building functional neural circuits, including the [positive regulation of dendrite morphogenesis](/details-go/GO:0050775), [positive regulation of dendritic spine morphogenesis](/details-go/GO:0061003), and [positive regulation of synapse assembly](/details-go/GO:0051965). The proper execution of these developmental programs underlies higher-order brain functions, which is reflected in its association with [cognition](/details-go/GO:0050890) and [short-term memory](/details-go/GO:0007614). The presence of the CUX2 protein in the [extracellular exosome](/details-go/GO:0070062) suggests a potential, less-characterized role in intercellular communication. ## Research Directions The strong association of [CUX2](/details-gene/23316) with neurodevelopmental disorders, coupled with its specific expression pattern, opens several avenues for future research. **Proposed Hypotheses:** 1. Recurrent missense variants linked to epilepsy ([Link](https://doi.org/10.1002/ana.25222)) impair the ability of [CUX2](/details-gene/23316) to properly regulate target genes involved in synaptic function within cortical [interneurons](/details-cell/CL0000099), leading to an excitatory/inhibitory imbalance and network hyperexcitability. 2. The high expression of [CUX2](/details-gene/23316) in [hepatocytes](/details-cell/CL0000182) indicates a previously uncharacterized role in liver biology, where it may regulate a distinct set of genes involved in metabolic pathways or xenobiotic response, a function independent of its role in the brain. 3. The detection of [CUX2](/details-gene/23316) protein in exosomes suggests it may be transported between cells, where it could function as a non-cell-autonomous signal to influence gene expression in recipient cells, such as astrocytes or microglia, thereby modulating the neuronal microenvironment. **Experimental Approach:** To test the primary hypothesis regarding the impact of disease-associated variants, an ideal approach would be to use patient-derived induced pluripotent stem cells (iPSCs). iPSCs carrying a pathogenic [CUX2](/details-gene/23316) variant and isogenic, CRISPR-corrected controls could be differentiated into cortical organoids containing relevant cell types like [pvalb GABAergic cortical interneurons](/details-cell/CL4023018). Subsequent multi-omic analysis, including single-cell RNA-seq and ATAC-seq, would reveal how the variant alters the transcriptional landscape and chromatin accessibility. Furthermore, functional assessments using multi-electrode arrays (MEAs) would directly measure changes in neuronal firing and network synchrony, linking the molecular defect to a quantifiable physiological phenotype. **Therapeutic Potential:** Given that [CUX2](/details-gene/23316) is a nuclear transcription factor, it represents a challenging target for direct pharmacological intervention with small molecules. The associated disorders appear to arise from loss-of-function or dominant-negative effects. Therefore, therapeutic strategies would likely focus on genetic-based correction rather than inhibition. Potential future approaches could include allele-specific oligonucleotide therapies designed to silence the mutant allele or gene therapies aimed at restoring functional CUX2 protein levels in affected neuronal populations.

Genular Protein ID: 575104695

Symbol: CUX2_HUMAN

Name: Homeobox protein cut-like 2

UniProtKB Accession Codes:

O14529 A7E2Y4

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 6 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 18 Gene3D 2 GeneCards 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 3 PDBsum 3 PRO 1 PROSITE 3 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 RefSeq 1 SIGNOR 1 SMART 2 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 2 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 9179496

Title: Construction and characterization of human brain cDNA libraries suitable for analysis of cDNA clones encoding relatively large proteins.

PubMed ID: 9179496

DOI: 10.1093/dnares/4.1.53

PubMed ID: 12168954

Title: Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones.

PubMed ID: 12168954

DOI: 10.1093/dnares/9.3.99

PubMed ID: 16541075

Title: The finished DNA sequence of human chromosome 12.

PubMed ID: 16541075

DOI: 10.1038/nature04569

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: 18669648

Title: A quantitative atlas of mitotic phosphorylation.

PubMed ID: 18669648

DOI: 10.1073/pnas.0805139105

PubMed ID: 29630738

Title: The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant.

PubMed ID: 29630738

DOI: 10.1002/ana.25222

PubMed ID: 29795476

Title: A recurrent de novo CUX2 missense variant associated with intellectual disability, seizures, and autism spectrum disorder.

PubMed ID: 29795476

DOI: 10.1038/s41431-018-0184-5

Sequence Information:

  • Length: 1486
  • Mass: 161677
  • Checksum: 71782EF5214D0262
  • Sequence:
    • MAANVGSMFQ YWKRFDLRRL QKELNSVASE LSARQEESEH SHKHLIELRR EFKKNVPEEI 
REMVAPVLKS FQAEVVALSK RSQEAEAAFL SVYKQLIEAP DPVPVFEAAR SLDDRLQPPS 
FDPSGQPRRD LHTSWKRNPE LLSPKEQREG TSPAGPTLTE GSRLPGIPGK ALLTETLLQR 
NEAEKQKGLQ EVQITLAARL GEAEEKIKVL HSALKATQAE LLELRRKYDE EAASKADEVG 
LIMTNLEKAN QRAEAAQREV ESLREQLASV NSSIRLACCS PQGPSGDKVN FTLCSGPRLE 
AALASKDREI LRLLKDVQHL QSSLQELEEA SANQIADLER QLTAKSEAIE KLEEKLQAQS 
DYEEIKTELS ILKAMKLASS TCSLPQGMAK PEDSLLIAKE AFFPTQKFLL EKPSLLASPE 
EDPSEDDSIK DSLGTEQSYP SPQQLPPPPG PEDPLSPSPG QPLLGPSLGP DGTRTFSLSP 
FPSLASGERL MMPPAAFKGE AGGLLVFPPA FYGAKPPTAP ATPAPGPEPL GGPEPADGGG 
GGAAGPGAEE EQLDTAEIAF QVKEQLLKHN IGQRVFGHYV LGLSQGSVSE ILARPKPWRK 
LTVKGKEPFI KMKQFLSDEQ NVLALRTIQV RQRGSITPRI RTPETGSDDA IKSILEQAKK 
EIESQKGGEP KTSVAPLSIA NGTTPASTSE DAIKSILEQA RREMQAQQQA LLEMEVAPRG 
RSVPPSPPER PSLATASQNG APALVKQEEG SGGPAQAPLP VLSPAAFVQS IIRKVKSEIG 
DAGYFDHHWA SDRGLLSRPY ASVSPSLSSS SSSGYSGQPN GRAWPRGDEA PVPPEDEAAA 
GAEDEPPRTG ELKAEGATAE AGARLPYYPA YVPRTLKPTV PPLTPEQYEL YMYREVDTLE 
LTRQVKEKLA KNGICQRIFG EKVLGLSQGS VSDMLSRPKP WSKLTQKGRE PFIRMQLWLS 
DQLGQAVGQQ PGASQASPTE PRSSPSPPPS PTEPEKSSQE PLSLSLESSK ENQQPEGRSS 
SSLSGKMYSG SQAPGGIQEI VAMSPELDTY SITKRVKEVL TDNNLGQRLF GESILGLTQG 
SVSDLLSRPK PWHKLSLKGR EPFVRMQLWL NDPHNVEKLR DMKKLEKKAY LKRRYGLIST 
GSDSESPATR SECPSPCLQP QDLSLLQIKK PRVVLAPEEK EALRKAYQLE PYPSQQTIEL 
LSFQLNLKTN TVINWFHNYR SRMRREMLVE GTQDEPDLDP SGGPGILPPG HSHPDPTPQS 
PDSETEDQKP TVKELELQEG PEENSTPLTT QDKAQVRIKQ EQMEEDAEEE AGSQPQDSGE 
LDKGQGPPKE EHPDPPGNDG LPKVAPGPLL PGGSTPDCPS LHPQQESEAG ERLHPDPLSF 
KSASESSRCS LEVSLNSPSA ASSPGLMMSV SPVPSSSAPI SPSPPGAPPA KVPSASPTAD 
MAGALHPSAK VNPNLQRRHE KMANLNNIIY RVERAANREE ALEWEF