SIX3

SIX3
Identifiers
Aliases	SIX3, HPE2, SIX homeobox 3
External IDs	OMIM: 603714 MGI: 102764 HomoloGene: 3947 GeneCards: SIX3
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2p21 Start 44,941,702 bp[1] End 44,946,071 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17 E4|17 55.42 cM Start 85,921,036 bp[2] End 85,936,730 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in retinal pigment epithelium nucleus accumbens optic nerve caudate nucleus putamen anterior pituitary external globus pallidus hypothalamus islet of Langerhans sperm Top expressed in optic vesicle pretectal area subthalamus zona incerta suprachiasmatic nucleus optic recess thalamic reticular nucleus nucleus accumbens medial habenular nucleus medial ganglionic eminence More reference expression data BioGPS More reference expression data
Gene ontology Molecular function RNA polymerase II cis-regulatory region sequence-specific DNA binding DNA binding sequence-specific DNA binding DNA-binding transcription factor activity transcription coactivator activity histone deacetylase binding DNA-binding transcription activator activity, RNA polymerase II-specific protein binding transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding transcription corepressor binding signaling receptor binding DNA-binding transcription factor activity, RNA polymerase II-specific transcription cis-regulatory region binding Cellular component nucleus transcription regulator complex Biological process eye development forebrain anterior/posterior pattern specification pituitary gland development regulation of transcription, DNA-templated negative regulation of neuron differentiation proximal/distal axis specification lens fiber cell apoptotic process protein import into nucleus neuroblast differentiation forebrain dorsal/ventral pattern formation optic vesicle morphogenesis negative regulation of Wnt signaling pathway apoptotic process involved in development transcription by RNA polymerase II regulation of neural precursor cell proliferation transcription, DNA-templated regulation of neural retina development multicellular organism development telencephalon regionalization diencephalon development telencephalon development brain development lens development in camera-type eye lens fiber cell differentiation regulation of cell population proliferation regulation of neuroblast proliferation lens induction in camera-type eye epithelial cell maturation neuroblast migration circadian behavior camera-type eye development negative regulation of transcription, DNA-templated cell proliferation in forebrain positive regulation of transcription by RNA polymerase II visual perception regulation of cell cycle phase transition anatomical structure development Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6496 20473 Ensembl ENSG00000138083 ENSMUSG00000038805 UniProt O95343 Q62233 RefSeq (mRNA) NM_005413 NM_011381 RefSeq (protein) NP_005404 NP_035511 Location (UCSC) Chr 2: 44.94 – 44.95 Mb Chr 17: 85.92 – 85.94 Mb PubMed search [3] [4]
Wikidata
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Homeobox protein SIX3 is a protein that in humans is encoded by the SIX3 gene.^[5][6][7]

Function

The SIX homeobox 3 (SIX3) gene is crucial in embryonic development by providing necessary instructions for the formation of the forebrain and eye development. SIX3 is a transcription factor that binds to specific DNA sequences, controlling whether the gene is active or inactive. Activity of the SIX3 gene represses Wnt1 gene activity which ensures development of the forebrain and establishes the proper anterior posterior identity in the mammalian brain. By blocking Wnt1 activity, SIX3 is able to prevent abnormal expansion of the posterior portion of the brain into the anterior brain area.

During retinal development, SIX3 has been proven to hold a key responsibility in the activation of Pax6, the master regulator of eye development. Furthermore, SIX3 assumes its activity in the PLE (presumptive lens ectoderm), the region in which the lens is expected to develop. If its presence is removed from this region, the lens fails to thicken and construct itself to its proper morphological state. Also, SIX3 plays a strategic role in the activation of SOX2.

SIX3 has also been proven to play a role in repression of selected members of the Wnt family. In retinal development, SIX3 is responsible for the repression of Wnt8b. Also, in forebrain development, SIX3 is responsible for the repression of Wnt1 and activation of SHH, Sonic Hedgehog gene.

Clinical significance

Mutations in SIX3 are the cause of a severe brain malformation, called holoprosencephaly type 2 (HPE2). In HPE2, the brain fails to separate into two hemispheres during early embryonic development, leading to eye and brain malformations, which result in serious facial abnormalities.^[6]

A mutant zebrafish knockout model has been developed, in which the anterior part of the head was missing due to the atypical increase of Wnt1 activity. When injected with SIX3, these zebrafish embryos were able to successfully develop a normal forebrain.^[8][9] When SIX3 was turned off in mice, it resulted in a lack of retina formation due to excessive expression of Wnt8b in the region where the forebrain normally develops.^[10] Both of these studies demonstrate the importance of SIX3 activity in brain and eye development.

Interactions

SIX3 has been shown to interact with TLE1^[11] and Neuron-derived orphan receptor 1.^[12][13]

References

Further reading

External links

• GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview