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Symbol OTX2 contributors: mct/npt/pgu/shn - updated : 04-04-2018
HGNC name orthodenticle homeobox 2
HGNC id 8522
Corresponding disease
AGOTC2 agnathia-otocephaly 2
DEL14Q22 chromosome 14q deletion, encompassing band q22
MCOP2 microphthalmia, isolated 2
MCOPS5 microphthalmia syndromic 5
Location 14q22.3      Physical location : 57.267.426 - 57.277.184
Synonym name
  • orthodenticle homolog 2 (Drosophila)
  • paired-like homeo domain encoding gene 2
  • Synonym symbol(s) MCOPS5, MGC45000
    TYPE functioning gene
    STRUCTURE 9.78 kb     5 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    text structure
  • a retina-specific OTX2 enhancer element active in immature developing photoreceptors
  • OTX2 expressions in anterior neuroectoderm and forebrain/midbrain are regulated by more than six enhancers located far from the coding region
  • MAPPING cloned Y linked   status provisional
    Map cen - D14S980 - D14S66 - OTX2 - D14S274 - D14S1038 - qter
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    3 splicing 2069 - 289 - 2013 23566845
    5 splicing 2196 - 297 - 2013 23566845
    4 - 2348 - 289 - 2013 23566845
    5 - 2195 - 289 - 2013 23566845
    3 - 2142 - 297 - 2013 23566845
    4 splicing - - - - 2013 23566845
  • lacks entire exon 4, most of the region encoding the homeodomain
  • harbors an early premature stop codon
    Type restricted
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Visualeyeretina  highly
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialbarrier liningretinal pigment epithelium (RPE)  
    SystemCellPubmedSpeciesStageRna symbol
    Visualbipolar cell Homo sapiens
    cell lineage
    cell lines
    at STAGE
    physiological period embryo, fetal, pregnancy
  • developing brain of the anterior neural plate in mouse, fetal eye
  • helix-turn-helix,DNA binding domain
  • a bicoid-like homeodomain
  • a 192-aa proline, serine and threonine-rich C-terminal region, which contains a highly conserved SIWSPA peptide sequence and a tandemly duplicated OTX tail
  • a WRPW peptide motif required for physical interaction between OTX2 and TLE4
    interspecies ortholog to Otx2, Mus musculus
    ortholog to otx2, Danio rerio
    ortholog to Otx2, Rattus norvegicus
    ortholog to OTX2, Pan troglodytes
  • paired homeobox family
  • bicoid subfamily
  • CATEGORY transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
  • localized to the nuclei of retinal pigment epithelium
  • in the bipolar cells, the exogenous OTX2 relocates to the mitochondria to support mitochondrial ATP synthesis
  • basic FUNCTION
  • playing a major role in gastrulation
  • essential for the early specification of neuroectoderm destined to become fore midbrain
  • involved in the formation of optic vesicle and retinogenesis
  • development of anterior neural plate specification and organization of the primitive streak
  • required for anterior brain, eye, and antenna formation and for regulating the development of photoreceptors and the expression of rhodopsin
  • transcription factor with an essential role in the development of the cerebellum
  • plays essential roles in the formation and patterning of the rostral brain
  • an essential regulator of the identity, extent and fate of neuronal progenitor domains in the ventral midbrain
  • may be a medulloblastoma oncogene
  • required for anterior neural plate induction, the region fated to become the anterior pituitary gland
  • involved in the pituitary function
  • may play a role in development of the retinal pigment epithelium and photoreceptor differentiation
  • required for regionalization and patterning of the developing brain and plays an important role in establishing the identity and fate of progenitor neurons
  • required for the formation of all forebrain- and midbrain-derived structures
  • OTX1 and OTX2 are important in neuronal cell development and differentiation: OTX1 primarily in the neocortex, and OTX2 in the archicortex, diencephalon, rostral brain stem, and cerebellum
  • controls neuron subtype identity by antagonizing molecular and functional features of dorsal-lateral ventral tegmental area and may antagonize vulnerability to the Parkinsonian toxin methyl-4-phenyl-1,2,3,6-tetrahydropyridine-HCl (
  • critical regulator of vertebrate photoreceptor genesis
  • regulates retinal photoreceptor cell fate determination
  • is required to maintain the embryonic stem cells (ESCs) metastable state by antagonizing ground state pluripotency and promoting commitment to differentiation
  • is a novel intrinsic determinant controlling the functional integrity of ESCs and epiblast stem cells (EpiSCs)
  • OTX2 is a molecular correlate of different pluripotent cell types
  • as in the embryo, OTX2 is crucially required to confer anterior character to ESC-derived neuroectoderm progenitors
  • acts as a master regulator of choroid plexuses (ChPs) development, thereby influencing one of the principal sources of signaling in the developing brain, the cerebrospinal fluid (CSF)
  • plays essential roles in each site at each step of head development
  • SOX6 and OTX2 control the specification of substantia nigra and ventral tegmental area dopamine neurons
  • is a homeodomain transcription factor that is necessary for normal head development
  • acts downstream of MYCN and is essential for patterning and spatial restriction of the sensory domain of the mammalian cochlea
  • plays a critical role in very early neurogenesis, but can become oncogenic when aberrantly expressed later in life
  • upon the induction of ESC differentiation, OTX2 alone or in combination with POU5F1 engages new enhancers, which are silent in undifferentiated ESCs
  • OTX2, ONECUT1 and possibly other Onecut proteins have likely a broad role in coordinating cone development and function
  • CELLULAR PROCESS nucleotide, transcription
    cell organization/biogenesis
    a component
    small molecule
  • LIM1 and HNF-3beta (
  • microphthalmia-associated transcription factor, MITF (
  • SOX2 (coordinate RAX expression in eye development, providing molecular linkages among the genes responsible for ocular malformation)
  • HESX1
  • represses Nkx2.2 in the ventral midbrain and maintains the Nkx6.1-expressing domain through dorsal antagonism on Shh (
  • GBX2 and OTX2 interact with the WD40 domain of Groucho/Tle corepressors
  • transcriptional repressor Otx3/Dmbx1 (
  • markedly transactivated the promoters of IRBP, HESX1, and POU1F1
  • MEIS2
  • TLE4
  • CRX, OTX2, and RORB directly regulate NRL transcription by binding to critical sites within the NRL promoter
  • OTX2 expression is activated by the class III POU factors in the forebrain and midbrain, whereas it is repressed by GBX2 in the hindbrain
  • GBX2 restricts the OTX2 expression to the forebrain/midbrain (FM) by directly binding to its FM enhancer, competing with the class III POU factors
  • OTX2 prevents the presumptive RPE region from forming the neural retina (NR) by repressing the expression of both FGF8 and SOX2 which induce the NR cell fate
  • OTX2 maintains NRL expression in developing rods to consolidate rod fate
  • OTX2 can interact with the H1 regulatory region of DKK1 to activate its expression
  • OTX2 regulates DKK1 and LHX1 activity in the anterior mesendoderm
  • OTX2 Requires LMX1B to control the development of mesodiencephalic dopaminergic neurons
  • OTX2 is a crucial target of MYCN during inner ear development, and MYCN may directly regulate OTX2
  • HMGA2 gene is activated by OTX2 and HMGA2 protein binds to the enhancers targeted by OTX2, thus facilitating the engagement and/or the stable association of OTX2
  • cell & other
    Other transcriptional activity is modulated by TLE4, a member of the Groucho-related-gene (Grg) family, modulation especially critical during puberty and in the control of the estrous cycle
    corresponding disease(s) MCOPS5 , DEL14Q22 , MCOP2 , AGOTC2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in medulloblastoma
    constitutional germinal mutation      
    acts as a dominant inhibitor of HESX1 that plays a critical role in pituitary development and leads to hypopituitarism
    constitutional     --over  
    increases GNRH1 promoter activity in GNRH1 neuronal cell lines
    tumoral     --low  
    resulted in decreased expression of MYC and CRX, genes previously implicated in retinoblastoma tumorigenesis
    tumoral     --other  
    aberrant expression of OTX2 may contribute to the development of retinoblastoma
    constitutional     --low  
    in the adult retina disrupts retinal pigment epithelium function, causing photoreceptor degeneration
    Susceptibility to bipolar disorder
    Variant & Polymorphism other variations might confer risk for the development of bipolar disorder
    Candidate gene
    Therapy target
    therapeutic potential of OTX2 protein transduction in retinal dystrophy
  • by ectopical expression of Otx2 in the presumptive anterior hindbrain using a knock-in mousestrategy into the En1 locus in, animals display a cerebellar ataxia, brains reveal that most of the anterior cerebellar vermis is missing, whereas the inferior colliculus is complementarily enlarged (
  • mice homozygous for Otx2 deficiency in early head development and pituitary oral ectoderm exhibit craniofacial defects and pituitary gland dysmorphology, but normal pituitary cell specification