Details for: SIX3

Gene ID: 6496

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: SIX3

Ensembl ID: ENSG00000138083

Description: SIX homeobox 3

Cell Significance Landscape

Associated with

Significant Cells

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

  • ionocyte CL0005006
    CSI 9.91
    rCSI 10.62%
    PRS 95
  • OFF-bipolar cell CL0000750
    CSI 7.02
    rCSI 9.6%
    PRS 92.13
  • retina horizontal cell CL0000745
    CSI 6.2
    rCSI 9.46%
    PRS 91.7
  • ciliated cell CL0000064
    CSI 5.65
    rCSI 9.15%
    PRS 88.94
  • retinal bipolar neuron CL0000748
    CSI 5.38
    rCSI 10.08%
    PRS 88.13
  • GABAergic amacrine cell CL4030027
    CSI 4.36
    rCSI 14.92%
    PRS 84.03
  • rod bipolar cell CL0000751
    CSI 3.35
    rCSI 6.01%
    PRS 90.43
  • retinal pigment epithelial cell CL0002586
    CSI 3.22
    rCSI 6.4%
    PRS 91.59
  • secretory cell CL0000151
    CSI 3.18
    rCSI 3.32%
    PRS 93.44
  • multi-ciliated epithelial cell CL0005012
    CSI 3.04
    rCSI 3.03%
    PRS 89.6
  • nasal mucosa goblet cell CL0002480
    CSI 2.98
    rCSI 3.46%
    PRS 94
  • ON-bipolar cell CL0000749
    CSI 2.74
    rCSI 4.08%
    PRS 92.7
  • retinal ganglion cell CL0000740
    CSI 2.7
    rCSI 5.97%
    PRS 86.45
  • Mueller cell CL0000636
    CSI 2.68
    rCSI 6.12%
    PRS 89.39
  • choroid plexus epithelial cell CL0000706
    CSI 2.66
    rCSI 4.35%
    PRS 89.12
  • neuroblast (sensu Nematoda and Protostomia) CL0000338
    CSI 2.24
    rCSI 2.59%
    PRS 88.02
  • glioblast CL0000030
    CSI 1.82
    rCSI 2.91%
    PRS 88.29
  • club cell CL0000158
    CSI 1.71
    rCSI 2.51%
    PRS 91.11
  • amacrine cell CL0000561
    CSI 1.68
    rCSI 4.87%
    PRS 87.87
  • glycinergic amacrine cell CL4030028
    CSI 1.56
    rCSI 4.06%
    PRS 89.29
  • type B pancreatic cell CL0000169
    CSI 1.3
    rCSI 2.87%
    PRS 94.04
  • H1 horizontal cell CL0004217
    CSI 1.16
    rCSI 4.61%
    PRS 89.29
  • H2 horizontal cell CL0004218
    CSI 1.08
    rCSI 5.37%
    PRS 89.77
  • diffuse bipolar 6 cell CL4033032
    CSI 1.08
    rCSI 5.66%
    PRS 85.65
  • diffuse bipolar 1 cell CL4033027
    CSI 0.85
    rCSI 6.42%
    PRS 84.57
  • cone retinal bipolar cell CL0000752
    CSI 0.8
    rCSI 10.42%
    PRS 90.23
  • indirect pathway medium spiny neuron CL4023029
    CSI 0.31
    rCSI 7.59%
    PRS 82.68
  • direct pathway medium spiny neuron CL4023026
    CSI 0.27
    rCSI 6.5%
    PRS 82.82

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)

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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 [SIX3](/details-gene/6496) is a homeobox-containing protein that functions as a DNA-binding transcription factor, playing a critical role in the embryonic development of the anterior central nervous system. It is essential for the proper formation of the forebrain, pituitary gland, and eyes. Gene ontology annotations highlight its involvement in processes such as [brain development](/details-go/GO:0007420), [eye development](/details-go/GO:0001654), and the negative regulation of transcription. Expression data reveals that **Overall**, [SIX3](/details-gene/6496) is a highly significant marker for a specific subset of neural and epithelial cells, particularly various neuronal subtypes within the retina, including [ionocyte](/details-cell/CL0005006), [OFF-bipolar cell](/details-cell/CL0000750), and [retina horizontal cell](/details-cell/CL0000745). Clinically, loss-of-function mutations in [SIX3](/details-gene/6496) are causally linked to holoprosencephaly-2 ([157170](https://omim.org/entry/157170)), a severe congenital disorder characterized by incomplete cleavage of the embryonic forebrain ([Link](https://doi.org/10.1038/9718)). ## Cellular Roles and Expression Landscape The expression profile of [SIX3](/details-gene/6496) points to a highly specialized function, predominantly within tissues derived from the neuroectoderm. **Overall**, the gene exhibits its highest significance in a consortium of cells essential for vision and neural processing within the eye. It is a defining marker for multiple classes of retinal neurons, including [retinal bipolar neuron](/details-cell/CL0000748), [retina horizontal cell](/details-cell/CL0000745), [GABAergic amacrine cell](/details-cell/CL4030027), and [retinal ganglion cell](/details-cell/CL0000740). Its prominence extends to supportive and associated ocular cells such as the [retinal pigment epithelial cell](/details-cell/CL0002586) and the glial [Mueller cell](/details-cell/CL0000636). This concentrated expression pattern suggests [SIX3](/details-gene/6496) acts as a key regulator in establishing the complex cellular architecture and circuitry of the retina. Beyond the eye, [SIX3](/details-gene/6496) is also significantly expressed in specialized epithelial cell populations, including [ionocyte](/details-cell/CL0005006), [ciliated cell](/details-cell/CL0000064), and [choroid plexus epithelial cell](/details-cell/CL0000706). The choroid plexus is responsible for producing cerebrospinal fluid, linking [SIX3](/details-gene/6496) back to central nervous system development and homeostasis. The common thread among these diverse cell types may relate to shared developmental origins or conserved regulatory networks governing specialized epithelial functions. ## Pathways and Molecular Function Functionally, [SIX3](/details-gene/6496) is a transcription factor that binds to DNA and modulates gene expression. Its molecular function annotations confirm its role in [Rna polymerase ii cis-regulatory region sequence-specific dna binding](/details-go/GO:0000978) and its ability to act as both a transcriptional activator and corepressor through protein-protein interactions ([Link](https://pubmed.ncbi.nlm.nih.gov/12543801)). For instance, its activity can be modulated by interaction with Groucho family corepressors ([Link](https://doi.org/10.1242/dev.00185)). The biological processes associated with [SIX3](/details-gene/6496) align precisely with its cellular expression and known pathology. Its involvement in [forebrain dorsal/ventral pattern formation](/details-go/GO:0021798) and [telencephalon development](/details-go/GO:0021537) provides a direct molecular basis for the holoprosencephaly phenotype observed upon its mutation ([Link](https://doi.org/10.1093/hmg/ddn294)). Similarly, its annotated roles in [regulation of neural retina development](/details-go/GO:0061074) and [lens development in camera-type eye](/details-go/GO:0002088) are consistent with its high significance in retinal cells and its interaction with other key eye development factors like geminin ([Link](https://doi.org/10.1038/nature02292)). Furthermore, its function in regulating the proliferation of neural precursors ([GO:2000177](/details-go/GO:2000177)) underscores its importance in controlling the pool of progenitor cells during nervous system formation. ## Research Directions The specific expression pattern and critical developmental functions of [SIX3](/details-gene/6496) offer several avenues for future investigation. **Proposed Hypotheses:** 1. Given its high significance across multiple, distinct classes of retinal interneurons (e.g., [bipolar cells](/details-cell/CL0000748), [horizontal cells](/details-cell/CL0000745), [amacrine cells](/details-cell/CL4030027)), it is hypothesized that [SIX3](/details-gene/6496) is a master regulator required for the terminal differentiation and subsequent maintenance of these specific neuronal identities. Its loss post-commitment would likely lead to cell death or a failure to maintain mature functional properties, thereby disrupting retinal information processing. 2. The shared high expression in disparate ciliated tissues, such as [ciliated cell](/details-cell/CL0000064) and [choroid plexus epithelial cell](/details-cell/CL0000706), suggests that [SIX3](/details-gene/6496) controls a core transcriptional program for ciliogenesis or ciliary function. It may regulate a common set of downstream target genes essential for the structure or motility of cilia in these diverse anatomical locations. **Experimental Approach for Hypothesis 1:** To test the role of [SIX3](/details-gene/6496) in maintaining retinal neuron identity, a conditional knockout mouse model could be employed. Using a tamoxifen-inducible Cre-recombinase system driven by a pan-retinal promoter (e.g., *Chx10-CreERT2*), the *Six3* gene could be deleted in retinal progenitor cells or mature retinal neurons in adult mice. The functional and structural consequences could be assessed using electroretinography (ERG) to measure retinal function, followed by immunohistochemical analysis and single-cell RNA sequencing of the retina to determine if specific neuronal populations are lost, de-differentiated, or altered in their gene expression profiles. **Therapeutic Potential:** The clinical relevance of [SIX3](/details-gene/6496) is rooted in developmental haploinsufficiency, where loss-of-function mutations cause severe congenital malformations. As such, therapeutic strategies would theoretically be aimed at **activation or restoration** of function, not inhibition. However, targeting a developmental transcription factor for therapeutic gain is exceptionally challenging. Its role is largely fulfilled during embryogenesis, making postnatal intervention for conditions like holoprosencephaly difficult. Therefore, the primary clinical utility of [SIX3](/details-gene/6496) remains in the realm of diagnostics and genetic counseling for families affected by developmental brain disorders. Future advances in gene therapy for in utero treatment of monogenic disorders could, in principle, be relevant, but this remains a distant and speculative possibility.

Genular Protein ID: 1435548606

Symbol: SIX3_HUMAN

Name: Homeobox protein SIX3

UniProtKB Accession Codes:

O95343 D6W5A5 Q53T42

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 7 Ensembl 1 GO 34 Gene3D 1 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 5 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 7 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 1 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 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 9889003

Title: Genomic cloning, structure, expression pattern, and chromosomal location of the human SIX3 gene.

PubMed ID: 9889003

DOI: 10.1006/geno.1998.5611

PubMed ID: 10415461

Title: Sequence and location of SIX3, a homeobox gene expressed in the human eye.

PubMed ID: 10415461

DOI: 10.1076/opge.20.1.7.2298

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

PubMed ID: 12543801

Title: The homeotic protein Six3 is a coactivator of the nuclear receptor NOR-1 and a corepressor of the fusion protein EWS/NOR-1 in human extraskeletal myxoid chondrosarcomas.

PubMed ID: 12543801

PubMed ID: 12441302

Title: Six3 and Six6 activity is modulated by members of the groucho family.

PubMed ID: 12441302

DOI: 10.1242/dev.00185

PubMed ID: 15523651

Title: Functional characterization of SIX3 homeodomain mutations in holoprosencephaly: interaction with the nuclear receptor NR4A3/NOR1.

PubMed ID: 15523651

DOI: 10.1002/humu.20102

PubMed ID: 14973488

Title: Direct interaction of geminin and Six3 in eye development.

PubMed ID: 14973488

DOI: 10.1038/nature02292

PubMed ID: 18775421

Title: Genetic interaction between the homeobox transcription factors HESX1 and SIX3 is required for normal pituitary development.

PubMed ID: 18775421

DOI: 10.1016/j.ydbio.2008.08.008

PubMed ID: 18791198

Title: Mutations in the human SIX3 gene in holoprosencephaly are loss of function.

PubMed ID: 18791198

DOI: 10.1093/hmg/ddn294

PubMed ID: 10369266

Title: Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly.

PubMed ID: 10369266

DOI: 10.1038/9718

PubMed ID: 15221788

Title: Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: mutation review and genotype-phenotype correlations.

PubMed ID: 15221788

DOI: 10.1002/humu.20056

PubMed ID: 17001667

Title: SIX3 mutations with holoprosencephaly.

PubMed ID: 17001667

DOI: 10.1002/ajmg.a.31377

PubMed ID: 20531442

Title: The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes.

PubMed ID: 20531442

DOI: 10.1038/ejhg.2010.70

PubMed ID: 20157829

Title: Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly.

PubMed ID: 20157829

DOI: 10.1007/s00439-010-0797-4

Sequence Information:

  • Length: 332
  • Mass: 35487
  • Checksum: 21EA07F6A2DD978F
  • Sequence:
    • MVFRSPLDLY SSHFLLPNFA DSHHRSILLA SSGGGNGAGG GGGAGGGSGG GNGAGGGGAG 
GAGGGGGGGS RAPPEELSMF QLPTLNFSPE QVASVCETLE ETGDIERLGR FLWSLPVAPG 
ACEAINKHES ILRARAVVAF HTGNFRDLYH ILENHKFTKE SHGKLQAMWL EAHYQEAEKL 
RGRPLGPVDK YRVRKKFPLP RTIWDGEQKT HCFKERTRSL LREWYLQDPY PNPSKKRELA 
QATGLTPTQV GNWFKNRRQR DRAAAAKNRL QHQAIGPSGM RSLAEPGCPT HGSAESPSTA 
ASPTTSVSSL TERADTGTSI LSVTSSDSEC DV