ID   PITX3_MOUSE             Reviewed;         302 AA.
AC   O35160; Q0VB03;
DT   15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT   01-JAN-1998, sequence version 1.
DT   24-JAN-2024, entry version 168.
DE   RecName: Full=Pituitary homeobox 3;
DE   AltName: Full=Homeobox protein PITX3;
DE   AltName: Full=Paired-like homeodomain transcription factor 3;
GN   Name=Pitx3;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Embryo, and Embryonic carcinoma;
RX   PubMed=9328475; DOI=10.1093/hmg/6.12.2109;
RA   Semina E.V., Reiter R.S., Murray J.C.;
RT   "Isolation of a new homeobox gene belonging to the Pitx/Rieg family:
RT   expression during lens development and mapping to the aphakia region on
RT   mouse chromosome 19.";
RL   Hum. Mol. Genet. 6:2109-2116(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain, and Testis;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [3]
RP   DEVELOPMENTAL STAGE.
RX   PubMed=9620774; DOI=10.1038/527;
RA   Semina E.V., Ferrell R.E., Mintz-Hittner H.A., Bitoun P., Alward W.L.M.,
RA   Reiter R.S., Funkhauser C., Daack-Hirsch S., Murray J.C.;
RT   "A novel homeobox gene PITX3 is mutated in families with autosomal-dominant
RT   cataracts and ASMD.";
RL   Nat. Genet. 19:167-170(1998).
RN   [4]
RP   FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX   PubMed=15950611; DOI=10.1016/j.ydbio.2005.03.028;
RA   Maxwell S.L., Ho H.Y., Kuehner E., Zhao S., Li M.;
RT   "Pitx3 regulates tyrosine hydroxylase expression in the substantia nigra
RT   and identifies a subgroup of mesencephalic dopaminergic progenitor neurons
RT   during mouse development.";
RL   Dev. Biol. 282:467-479(2005).
RN   [5]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=17184956; DOI=10.1016/j.ijdevneu.2006.11.003;
RA   Messmer K., Remington M.P., Skidmore F., Fishman P.S.;
RT   "Induction of tyrosine hydroxylase expression by the transcription factor
RT   Pitx3.";
RL   Int. J. Dev. Neurosci. 25:29-37(2007).
RN   [6]
RP   FUNCTION, AND DISEASE.
RX   PubMed=19334279; DOI=10.1002/dvdy.21924;
RA   Medina-Martinez O., Shah R., Jamrich M.;
RT   "Pitx3 controls multiple aspects of lens development.";
RL   Dev. Dyn. 238:2193-2201(2009).
RN   [7]
RP   FUNCTION, AND INTERACTION WITH SFPQ.
RX   PubMed=19144721; DOI=10.1242/dev.029769;
RA   Jacobs F.M., van Erp S., van der Linden A.J., von Oerthel L., Burbach J.P.,
RA   Smidt M.P.;
RT   "Pitx3 potentiates Nurr1 in dopamine neuron terminal differentiation
RT   through release of SMRT-mediated repression.";
RL   Development 136:531-540(2009).
RN   [8]
RP   FUNCTION, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX   PubMed=19007884; DOI=10.1016/j.mod.2008.10.007;
RA   Ho H.Y., Chang K.H., Nichols J., Li M.;
RT   "Homeodomain protein Pitx3 maintains the mitotic activity of lens
RT   epithelial cells.";
RL   Mech. Dev. 126:18-29(2009).
CC   -!- FUNCTION: Transcriptional regulator which is important for the
CC       differentiation and maintenance of meso-diencephalic dopaminergic
CC       (mdDA) neurons during development. In addition to its importance during
CC       development, it also has roles in the long-term survival and
CC       maintenance of the mdDA neurons. Activates NR4A2/NURR1-mediated
CC       transcription of genes such as SLC6A3, SLC18A2, TH and DRD2 which are
CC       essential for development of mdDA neurons. Acts by decreasing the
CC       interaction of NR4A2/NURR1 with the corepressor NCOR2/SMRT which acts
CC       through histone deacetylases (HDACs) to keep promoters of NR4A2/NURR1
CC       target genes in a repressed deacetylated state. Essential for the
CC       normal lens development and differentiation. Plays a critical role in
CC       the maintenance of mitotic activity of lens epithelial cells, fiber
CC       cell differentiation and in the control of the temporal and spatial
CC       activation of fiber cell-specific crystallins. Positively regulates
CC       FOXE3 expression and negatively regulates PROX1 in the anterior lens
CC       epithelium, preventing activation of CDKN1B/P27Kip1 and CDKN1C/P57Kip2
CC       and thus maintains lens epithelial cells in cell cycle.
CC       {ECO:0000269|PubMed:15950611, ECO:0000269|PubMed:17184956,
CC       ECO:0000269|PubMed:19007884, ECO:0000269|PubMed:19144721,
CC       ECO:0000269|PubMed:19334279}.
CC   -!- SUBUNIT: Interacts with SFPQ. {ECO:0000269|PubMed:19144721}.
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00108,
CC       ECO:0000255|PROSITE-ProRule:PRU00138, ECO:0000269|PubMed:17184956}.
CC   -!- TISSUE SPECIFICITY: Highly expressed in developing eye lens. Expression
CC       is restricted to the substantia nigra and ventral tegmental area in the
CC       midbrain. {ECO:0000269|PubMed:15950611, ECO:0000269|PubMed:19007884}.
CC   -!- DEVELOPMENTAL STAGE: First visible in 10.5 dpc embryos where expression
CC       is confined to the lens vesicles. Between 11.5 dpc and 12.5 dpc,
CC       expressed in both the lens epithelium and differentiating primary fiber
CC       cells. In the late fetal stage after the lens is formed, primarily
CC       found in the lens epithelium and the lens equator region where lens
CC       epithelial cells exit from the cell cycle and differentiate into fiber
CC       cells (at protein level). First expressed in the eye at 10 dpc embryos.
CC       Throughout eye development, expressed in the lens placode and forming
CC       lens pit. From 12 dpc, also detected in the midbrain region, tongue,
CC       incisor primordia, condensing mesenchyme around the sternum and
CC       vertebrae and in the head muscles. {ECO:0000269|PubMed:19007884,
CC       ECO:0000269|PubMed:9620774}.
CC   -!- DISEASE: Note=Mutations in Pitx3 appear to be the cause of the aphakia
CC       (ak) phenotype, a recessive homozygous disease characterized by small
CC       eyes and closed eyelids. {ECO:0000269|PubMed:19334279}.
CC   -!- DISRUPTION PHENOTYPE: Mice show loss of nascent substantia nigra
CC       dopaminergic neurons at the beginning of their final differentiation
CC       and a loss of tyrosine hydroxylase (TH) expression specifically in the
CC       substantia nigra neurons. {ECO:0000269|PubMed:15950611}.
CC   -!- SIMILARITY: Belongs to the paired homeobox family. Bicoid subfamily.
CC       {ECO:0000305}.
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DR   EMBL; AF005772; AAB87380.1; -; mRNA.
DR   EMBL; BC120844; AAI20845.1; -; mRNA.
DR   EMBL; BC137810; AAI37811.1; -; mRNA.
DR   CCDS; CCDS29872.1; -.
DR   RefSeq; NP_032878.1; NM_008852.4.
DR   AlphaFoldDB; O35160; -.
DR   BMRB; O35160; -.
DR   SMR; O35160; -.
DR   BioGRID; 202188; 1.
DR   IntAct; O35160; 1.
DR   STRING; 10090.ENSMUSP00000026259; -.
DR   PhosphoSitePlus; O35160; -.
DR   PaxDb; 10090-ENSMUSP00000026259; -.
DR   ProteomicsDB; 289587; -.
DR   Antibodypedia; 18010; 251 antibodies from 35 providers.
DR   DNASU; 18742; -.
DR   Ensembl; ENSMUST00000026259.16; ENSMUSP00000026259.10; ENSMUSG00000025229.16.
DR   GeneID; 18742; -.
DR   KEGG; mmu:18742; -.
DR   UCSC; uc008hsl.1; mouse.
DR   AGR; MGI:1100498; -.
DR   CTD; 5309; -.
DR   MGI; MGI:1100498; Pitx3.
DR   VEuPathDB; HostDB:ENSMUSG00000025229; -.
DR   eggNOG; KOG0486; Eukaryota.
DR   GeneTree; ENSGT00940000161801; -.
DR   HOGENOM; CLU_030301_0_0_1; -.
DR   InParanoid; O35160; -.
DR   OMA; NHTLSAC; -.
DR   OrthoDB; 5395268at2759; -.
DR   PhylomeDB; O35160; -.
DR   TreeFam; TF351940; -.
DR   BioGRID-ORCS; 18742; 0 hits in 80 CRISPR screens.
DR   PRO; PR:O35160; -.
DR   Proteomes; UP000000589; Chromosome 19.
DR   RNAct; O35160; Protein.
DR   Bgee; ENSMUSG00000025229; Expressed in lens of camera-type eye and 69 other cell types or tissues.
DR   ExpressionAtlas; O35160; baseline and differential.
DR   GO; GO:0000785; C:chromatin; ISO:MGI.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:NTNU_SB.
DR   GO; GO:0003700; F:DNA-binding transcription factor activity; ISO:MGI.
DR   GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR   GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
DR   GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
DR   GO; GO:0009653; P:anatomical structure morphogenesis; IBA:GO_Central.
DR   GO; GO:1990792; P:cellular response to glial cell derived neurotrophic factor; IEA:Ensembl.
DR   GO; GO:0071542; P:dopaminergic neuron differentiation; IDA:UniProtKB.
DR   GO; GO:0002088; P:lens development in camera-type eye; IMP:UniProtKB.
DR   GO; GO:0070306; P:lens fiber cell differentiation; IMP:UniProtKB.
DR   GO; GO:0002089; P:lens morphogenesis in camera-type eye; IMP:UniProtKB.
DR   GO; GO:0007626; P:locomotory behavior; IMP:MGI.
DR   GO; GO:0030901; P:midbrain development; IMP:UniProtKB.
DR   GO; GO:0014014; P:negative regulation of gliogenesis; ISO:MGI.
DR   GO; GO:0050768; P:negative regulation of neurogenesis; ISO:MGI.
DR   GO; GO:0048666; P:neuron development; IMP:MGI.
DR   GO; GO:1904935; P:positive regulation of cell proliferation in midbrain; ISO:MGI.
DR   GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB.
DR   GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISO:MGI.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:NTNU_SB.
DR   GO; GO:0006355; P:regulation of DNA-templated transcription; IDA:UniProtKB.
DR   GO; GO:0010468; P:regulation of gene expression; IDA:MGI.
DR   GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR   GO; GO:0042220; P:response to cocaine; IEA:Ensembl.
DR   GO; GO:0035902; P:response to immobilization stress; IEA:Ensembl.
DR   GO; GO:1904313; P:response to methamphetamine hydrochloride; IEA:Ensembl.
DR   CDD; cd00086; homeodomain; 1.
DR   Gene3D; 1.10.10.60; Homeodomain-like; 1.
DR   InterPro; IPR009057; Homeobox-like_sf.
DR   InterPro; IPR017970; Homeobox_CS.
DR   InterPro; IPR001356; Homeobox_dom.
DR   InterPro; IPR016233; Homeobox_Pitx/unc30.
DR   InterPro; IPR003654; OAR_dom.
DR   PANTHER; PTHR45882:SF2; PITUITARY HOMEOBOX 3; 1.
DR   PANTHER; PTHR45882; PITUITARY HOMEOBOX HOMOLOG PTX1; 1.
DR   Pfam; PF00046; Homeodomain; 1.
DR   Pfam; PF03826; OAR; 1.
DR   PIRSF; PIRSF000563; Homeobox_protein_Pitx/Unc30; 1.
DR   SMART; SM00389; HOX; 1.
DR   SUPFAM; SSF46689; Homeodomain-like; 1.
DR   PROSITE; PS00027; HOMEOBOX_1; 1.
DR   PROSITE; PS50071; HOMEOBOX_2; 1.
DR   PROSITE; PS50803; OAR; 1.
DR   Genevisible; O35160; MM.
PE   1: Evidence at protein level;
KW   Activator; Developmental protein; DNA-binding; Homeobox; Nucleus;
KW   Phosphoprotein; Reference proteome; Transcription;
KW   Transcription regulation.
FT   CHAIN           1..302
FT                   /note="Pituitary homeobox 3"
FT                   /id="PRO_0000049230"
FT   DNA_BIND        62..121
FT                   /note="Homeobox"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00108"
FT   REGION          1..71
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           262..275
FT                   /note="OAR"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00138"
FT   MOTIF           268..272
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000255"
FT   MOD_RES         52
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P81062"
FT   MOD_RES         57
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P81062"
SQ   SEQUENCE   302 AA;  31715 MW;  EB6EF6863B349264 CRC64;
     MEFGLLGEAE ARSPALSLSD AGTPHPPLPE HGCKGQEHSD SEKASASLPG GSPEDGSLKK
     KQRRQRTHFT SQQLQELEAT FQRNRYPDMS TREEIAVWTN LTEARVRVWF KNRRAKWRKR
     ERSQQAELCK GGFAAPLGGL VPPYEEVYPG YSYGNWPPKA LAPPLAAKTF PFAFNSVNVG
     PLASQPVFSP PSSIAASMVP SAAAAPGTVP GPGALQGLGG APPGLAPAAV SSGAVSCPYA
     SAAAAAAAAA SSPYVYRDPC NSSLASLRLK AKQHASFSYP AVPGPPPAAN LSPCQYAVER
     PV
//