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FLASH GENE
Symbol OTX2 contributors: mct/npt/pgu/shn - updated : 04-04-2016
HGNC name orthodenticle homeobox 2
HGNC id 8522
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • 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
  • HOMOLOGY
    interspecies ortholog to Otx2, Mus musculus
    ortholog to otx2, Danio rerio
    ortholog to Otx2, Rattus norvegicus
    ortholog to OTX2, Pan troglodytes
    Homologene
    FAMILY
  • paired homeobox family
  • bicoid subfamily
  • CATEGORY transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus
    text
  • 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
  • CELLULAR PROCESS nucleotide, transcription
    cell organization/biogenesis
    PHYSIOLOGICAL PROCESS development
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • 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
    REGULATION
    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
    ASSOCIATED DISORDERS
    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
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurosensorialvisualretina
    therapeutic potential of OTX2 protein transduction in retinal dystrophy
    ANIMAL & CELL MODELS
  • 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