Orthodenticle homeobox 2: Difference between revisions

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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
'''Homeobox protein OTX2''' is a [[protein]] that in humans is encoded by the ''OTX2'' [[gene]].<ref name="pmid7959790">{{cite journal | vauthors = Kastury K, Druck T, Huebner K, Barletta C, Acampora D, Simeone A, Faiella A, Boncinelli E | title = Chromosome locations of human EMX and OTX genes | journal = Genomics | volume = 22 | issue = 1 | pages = 41–5 | date = July 1994 | pmid = 7959790 | pmc =  | doi = 10.1006/geno.1994.1343 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: OTX2 orthodenticle homeobox 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5015| accessdate = }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image = PBB_Protein_OTX2_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 2dms.
| PDB = {{PDB2|2dms}}
| Name = Orthodenticle homeobox 2
| HGNCid = 8522
| Symbol = OTX2
| AltSymbols =; MCOPS5; MGC45000
| OMIM = 600037
| ECnumber = 
| Homologene = 11026
| MGIid = 97451
| GeneAtlas_image1 = PBB_GE_OTX2_gnf1h00384_at_tn.png
| Function = {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0008190 |text = eukaryotic initiation factor 4E binding}} {{GNF_GO|id=GO:0043565 |text = sequence-specific DNA binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0001708 |text = cell fate specification}} {{GNF_GO|id=GO:0006357 |text = regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0007275 |text = multicellular organismal development}} {{GNF_GO|id=GO:0007417 |text = central nervous system development}} {{GNF_GO|id=GO:0008589 |text = regulation of smoothened signaling pathway}} {{GNF_GO|id=GO:0009887 |text = organ morphogenesis}} {{GNF_GO|id=GO:0009952 |text = anterior/posterior pattern formation}} {{GNF_GO|id=GO:0009953 |text = dorsal/ventral pattern formation}} {{GNF_GO|id=GO:0030900 |text = forebrain development}} {{GNF_GO|id=GO:0030901 |text = midbrain development}} {{GNF_GO|id=GO:0040036 |text = regulation of fibroblast growth factor receptor signaling pathway}} {{GNF_GO|id=GO:0042706 |text = eye photoreceptor cell fate commitment}} {{GNF_GO|id=GO:0048663 |text = neuron fate commitment}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 5015
    | Hs_Ensembl = ENSG00000165588
    | Hs_RefseqProtein = NP_068374
    | Hs_RefseqmRNA = NM_021728
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 14
    | Hs_GenLoc_start = 56337182
    | Hs_GenLoc_end = 56346940
    | Hs_Uniprot = P32243
    | Mm_EntrezGene = 18424
    | Mm_Ensembl = ENSMUSG00000021848
    | Mm_RefseqmRNA = NM_144841
    | Mm_RefseqProtein = NP_659090
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 14
    | Mm_GenLoc_start = 47580137
    | Mm_GenLoc_end = 47589457
    | Mm_Uniprot = Q8R0B5
  }}
}}
'''Orthodenticle homeobox 2''', also known as '''OTX2''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: OTX2 orthodenticle homeobox 2| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5015| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
This gene encodes a member of the [[bicopid (gene)|bicoid]] sub-family of [[homeodomain]]-containing [[transcription factor]]s. The encoded protein acts as a transcription factor and may play a role in brain and sensory organ development. A similar protein in mice is required for proper forebrain development. Two transcript variants encoding distinct isoforms have been identified for this gene. Other alternative splice variants may exist, but their full length sequences have not been determined.<ref name="entrez"/>
{{PBB_Summary
| section_title =
| summary_text = This gene encodes a member of the bicoid sub-family of homeodomain-containing transcription factors. The encoded protein acts as a transcription factor and may play a role in brain and sensory organ development. A similar protein in mice is required for proper forebrain development. Two transcript variants encoding distinct isoforms have been identified for this gene. Other alternative splice variants may exist, but their full length sequences have not been determined.<ref name="entrez">{{cite web | title = Entrez Gene: OTX2 orthodenticle homeobox 2| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5015| accessdate = }}</ref>
}}


==References==
Otx2 is a group of homeobox genes that are typically described as a head organizer in the primitive streak stage of embryonic development. Otx2, which is an encoded protein that plays the role of a transcription factor, has also been shown to be involved in the regional [[patterns in nature|patterning]] of the [[midbrain]] and [[forebrain]]. This group of genes demonstrates later in progression to have an influence on the formation of the sensory organs, [[pituitary gland]], [[pineal gland]], [[inner ear]], eye and [[optic nerve]]. Otx2 not only has a prominent role in developing this area but also aids in ensuring that the [[retina]] and brain stay intact. This group of genes has a huge role in development and if it is expressed incorrectly it can have detrimental effects on the [[fetus]].   Otx2 mutations have also been associated with seizures, developmental delays, short stature, structural abnormalities of the pituitary gland, and an early onset of degeneration of the retina. A “[[gene knockout|knockout]]” model on the group of Otx2 genes has been performed to see what effects it would have on the adult retina. It was found that without the Otx2 gene expression there was slow degeneration of photoreceptor cells in this area. Thus, proving that the homeobox genes of Otx2 are essential in forming a viable embryo.
{{reflist|2}}
 
==Further reading==
== Clinical significance ==
{{refbegin | 2}}
 
{{PBB_Further_reading
Otx2 is expressed in the brain, ear, nose and eye, and in the case of mutations; it can lead to significant developmental abnormalities and disorders. Mutations in OTX2 can cause eye disorders including [[anophthalmia]] and [[microphthalmia]].<ref>{{cite journal | vauthors = Verma AS, Fitzpatrick DR | title = Anophthalmia and microphthalmia | journal = Orphanet Journal of Rare Diseases | volume = 2 | issue = | pages = 47 | date = November 2007 | pmid = 18039390 | pmc = 2246098 | doi = 10.1186/1750-1172-2-47 }}</ref> Apart from anophthalmia and microphthalmia, other abnormalities such as aplasia of the optic nerve, hypoplasia of the optic chiasm and dysplastic optic globes have also been observed. Other defects that occur due to a mutation of the Otx2 gene include pituitary abnormalities and mental retardation. Abnormal pituitary structure and/or function seem to be the most common feature associated with Otx2 mutations.<ref>{{cite journal | vauthors = Schilter KF, Schneider A, Bardakjian T, Soucy JF, Tyler RC, Reis LM, Semina EV | title = OTX2 microphthalmia syndrome: four novel mutations and delineation of a phenotype | journal = Clinical Genetics | volume = 79 | issue = 2 | pages = 158–68 | date = February 2011 | pmid = 20486942 | doi = 10.1111/j.1399-0004.2010.01450.x | pmc = 3017659 }}</ref>
| citations =
 
*{{cite journal | author=Hever AM, Williamson KA, van Heyningen V |title=Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2. |journal=Clin. Genet. |volume=69 |issue= 6 |pages= 459-70 |year= 2007 |pmid= 16712695 |doi= 10.1111/j.1399-0004.2006.00619.x }}
Otx2 also regulates two other genes, Lhx1 and Dkk1 that also play a role in head morphogenesis.<ref>{{cite journal | vauthors = Ip CK, Fossat N, Jones V, Lamonerie T, Tam PP | title = Head formation: OTX2 regulates Dkk1 and Lhx1 activity in the anterior mesendoderm | journal = Development | volume = 141 | issue = 20 | pages = 3859–67 | date = October 2014 | pmid = 25231759 | doi = 10.1242/dev.114900 }}</ref> Otx2 is required during early formation of the embryo to initiate the movement of cells towards the anterior region and establish the anterior visceral endoderm. In the absence of Otx2, this movement can be impeded, which can be overcome by the expression of Dkk1, but it does not prevent the embryo from developing head truncation defects. The absence of Otx2 and the enhanced expression of Lhx1 can also lead to severe head truncation.
*{{cite journal  | author=Kastury K, Druck T, Huebner K, ''et al.'' |title=Chromosome locations of human EMX and OTX genes. |journal=Genomics |volume=22 |issue= 1 |pages= 41-5 |year= 1994 |pmid= 7959790 |doi= 10.1006/geno.1994.1343 }}
 
*{{cite journal  | author=Simeone A, Acampora D, Mallamaci A, ''et al.'' |title=A vertebrate gene related to orthodenticle contains a homeodomain of the bicoid class and demarcates anterior neuroectoderm in the gastrulating mouse embryo. |journal=EMBO J. |volume=12 |issue= 7 |pages= 2735-47 |year= 1993 |pmid= 8101484 |doi= }}
It has been shown that if Otx2 is over expressed it can lead to childhood malignant brain tumors called [[medulloblastoma]]s.
*{{cite journal | author=Nagao T, Leuzinger S, Acampora D, ''et al.'' |title=Developmental rescue of Drosophila cephalic defects by the human Otx genes. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue= 7 |pages= 3737-42 |year= 1998 |pmid= 9520436 |doi= }}
 
*{{cite journal  | author=Bobola N, Briata P, Ilengo C, ''et al.'' |title=OTX2 homeodomain protein binds a DNA element necessary for interphotoreceptor retinoid binding protein gene expression. |journal=Mech. Dev. |volume=82 |issue= 1-2 |pages= 165-9 |year= 1999 |pmid= 10354480 |doi=  }}
Duplication of [[OTX2]] is involved in the [[pathogenesis]] of {{SWL|type=mutation_results_in|target=Hemifacial Microsomia|label=Hemifacial Microsomia}}.<ref>{{cite journal | vauthors = Zielinski D, Markus B, Sheikh M, Gymrek M, Chu C, Zaks M, Srinivasan B, Hoffman JD, Aizenbud D, Erlich Y | title = OTX2 duplication is implicated in hemifacial microsomia | journal = PLoS One | volume = 9 | issue = 5 | pages = e96788 | year = 2014 | pmid = 24816892 | pmc = 4016008 | doi = 10.1371/journal.pone.0096788 | bibcode = 2014PLoSO...996788Z }}</ref>
*{{cite journal | author=Fong SL, Fong WB |title=Elements regulating the transcription of human interstitial retinoid-binding protein (IRBP) gene in cultured retinoblastoma cells. |journal=Curr. Eye Res. |volume=18 |issue= 4 |pages= 283-91 |year= 1999 |pmid= 10372988 |doi= }}
 
*{{cite journal  | author=Nakano T, Murata T, Matsuo I, Aizawa S |title=OTX2 directly interacts with LIM1 and HNF-3beta. |journal=Biochem. Biophys. Res. Commun. |volume=267 |issue= 1 |pages= 64-70 |year= 2000 |pmid= 10623575 |doi= 10.1006/bbrc.1999.1872 }}
In the mouse, the lack of Otx2 inhibits the development of the head. These 'knockout' mice that fail to form the head have gastrulation defects and die at midgestation with severe brain anomalies.
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
 
*{{cite journal  | author=Takeda K, Yokoyama S, Yasumoto K, ''et al.'' |title=OTX2 regulates expression of DOPAchrome tautomerase in human retinal pigment epithelium. |journal=Biochem. Biophys. Res. Commun. |volume=300 |issue= 4 |pages= 908-14 |year= 2003 |pmid= 12559959 |doi= }}
==Role of Otx2 in Visual Plasticity==
*{{cite journal  | author=Martínez-Morales JR, Dolez V, Rodrigo I, ''et al.'' |title=OTX2 activates the molecular network underlying retina pigment epithelium differentiation. |journal=J. Biol. Chem. |volume=278 |issue= 24 |pages= 21721-31 |year= 2003 |pmid= 12663655 |doi= 10.1074/jbc.M301708200 }}
Recent research has identified the homeoprotein Otx2 as a possible molecular ‘messenger’ that is necessary for experience-driven visual [[neuroplasticity|plasticity]] during the [[critical period]].<ref>{{cite journal | vauthors = Sugiyama S, Prochiantz A, Hensch TK | title = From brain formation to plasticity: insights on Otx2 homeoprotein | journal = Development, Growth & Differentiation | volume = 51 | issue = 3 | pages = 369–77 | date = April 2009 | pmid = 19298552 | doi = 10.1111/j.1440-169X.2009.01093.x }}</ref> Initially involved in embryonic head formation, Otx2 is re-expressed during the [[critical period]] of rats (>P23) and regulates the maturation of [[parvalbumin]]-expressing [[GABA]]ergic interneurons (PV-cells), which control the onset of [[critical period]] [[neuroplasticity|plasticity]].<ref name="ReferenceA">{{cite journal | vauthors = Sugiyama S, Di Nardo AA, Aizawa S, Matsuo I, Volovitch M, Prochiantz A, Hensch TK | title = Experience-dependent transfer of Otx2 homeoprotein into the visual cortex activates postnatal plasticity | journal = Cell | volume = 134 | issue = 3 | pages = 508–20 | date = August 2008 | pmid = 18692473 | doi = 10.1016/j.cell.2008.05.054 }}</ref> Dark-rearing from birth and binocular [[enucleation (surgery)|enucleation]] of rats resulted in decreased expression of PV-cells and Otx2, which suggests that these proteins are visually experience-driven.<ref name="ReferenceA"/> Otx2 loss-of-function experiments delayed ocular dominance plasticity by impairing the development of PV-cells.<ref name="ReferenceA"/> Research into Otx2 and visual [[neuroplasticity|plasticity]] during the [[critical period]] is of particular interest to the study of developmental abnormalities such as [[amblyopia]]. More research must be conducted to determine if Otx2 could be utilized for therapeutic recovery of visual [[Neuroplasticity|plasticity]] to aid some [[amblyopia|amblyopic]] patients.
*{{cite journal | author=Puelles E, Annino A, Tuorto F, ''et al.'' |title=Otx2 regulates the extent, identity and fate of neuronal progenitor domains in the ventral midbrain. |journal=Development |volume=131 |issue= 9 |pages= 2037-48 |year= 2004 |pmid= 15105370 |doi= 10.1242/dev.01107 }}
 
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
== References ==
*{{cite journal | author=Boon K, Eberhart CG, Riggins GJ |title=Genomic amplification of orthodenticle homologue 2 in medulloblastomas. |journal=Cancer Res. |volume=65 |issue= 3 |pages= 703-7 |year= 2005 |pmid= 15705863 |doi=  }}
{{reflist}}
*{{cite journal | author=Di C, Liao S, Adamson DC, ''et al.'' |title=Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid. |journal=Cancer Res. |volume=65 |issue= 3 |pages= 919-24 |year= 2005 |pmid= 15705891 |doi=  }}
 
*{{cite journal | author=Ragge NK, Brown AG, Poloschek CM, ''et al.'' |title=Heterozygous mutations of OTX2 cause severe ocular malformations. |journal=Am. J. Hum. Genet. |volume=76 |issue= 6 |pages= 1008-22 |year= 2005 |pmid= 15846561 |doi= 10.1086/430721 }}
== Further reading ==
*{{cite journal | author=Brunet I, Weinl C, Piper M, ''et al.'' |title=The transcription factor Engrailed-2 guides retinal axons. |journal=Nature |volume=438 |issue= 7064 |pages= 94-8 |year= 2005 |pmid= 16267555 |doi= 10.1038/nature04110 }}
{{refbegin|33em}}
*{{cite journal | author=Chatelain G, Fossat N, Brun G, Lamonerie T |title=Molecular dissection reveals decreased activity and not dominant negative effect in human OTX2 mutants. |journal=J. Mol. Med. |volume=84 |issue= 7 |pages= 604-15 |year= 2007 |pmid= 16607563 |doi= 10.1007/s00109-006-0048-2 }}
* {{cite journal | vauthors = Millet S, Bloch-Gallego E, Simeone A, Alvarado-Mallart RM | title = The caudal limit of Otx2 gene expression as a marker of the midbrain/hindbrain boundary: a study using in situ hybridisation and chick/quail homotopic grafts | journal = Development | volume = 122 | issue = 12 | pages = 3785–97 | date = December 1996 | pmid = 9012500 | doi = }}
*{{cite journal | author=Lim J, Hao T, Shaw C, ''et al.'' |title=A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. |journal=Cell |volume=125 |issue= 4 |pages= 801-14 |year= 2006 |pmid= 16713569 |doi= 10.1016/j.cell.2006.03.032 }}
* {{cite journal | vauthors = Larsen KB, Lutterodt MC, Møllgård K, Møller M | title = Expression of the homeobox genes OTX2 and OTX1 in the early developing human brain | journal = The Journal of Histochemistry and Cytochemistry | volume = 58 | issue = 7 | pages = 669–78 | date = July 2010 | pmid = 20354145 | pmc = 2889402 | doi = 10.1369/jhc.2010.955757 }}
*{{cite journal | author=Heimbucher T, Murko C, Bajoghli B, ''et al.'' |title=Gbx2 and Otx2 interact with the WD40 domain of Groucho/Tle corepressors. |journal=Mol. Cell. Biol. |volume=27 |issue= 1 |pages= 340-51 |year= 2007 |pmid= 17060451 |doi= 10.1128/MCB.00811-06 }}
* {{cite journal | vauthors = Kimura C, Takeda N, Suzuki M, Oshimura M, Aizawa S, Matsuo I | title = Cis-acting elements conserved between mouse and pufferfish Otx2 genes govern the expression in mesencephalic neural crest cells | journal = Development | volume = 124 | issue = 20 | pages = 3929–41 | date = October 1997 | pmid = 9374391 | doi =  }}
}}
* {{cite journal | vauthors = Gat-Yablonski G | title = Brain development is a multi-level regulated process--the case of the OTX2 gene | journal = Pediatric Endocrinology Reviews | volume = 9 | issue = 1 | pages = 422–30 | date = September 2011 | pmid = 22783640 | doi =  }}
* {{cite journal | vauthors = Béby F, Housset M, Fossat N, Le Greneur C, Flamant F, Godement P, Lamonerie T | title = Otx2 gene deletion in adult mouse retina induces rapid RPE dystrophy and slow photoreceptor degeneration | journal = PLoS One | volume = 5 | issue = 7 | pages = e11673 | year = 2010 | pmid = 20657788 | pmc = 2908139 | doi = 10.1371/journal.pone.0011673 | bibcode = 2010PLoSO...511673B }}
* {{cite journal | vauthors = Hever AM, Williamson KA, van Heyningen V | title = Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2 | journal = Clinical Genetics | volume = 69 | issue = 6 | pages = 459–70 | date = June 2006 | pmid = 16712695 | doi = 10.1111/j.1399-0004.2006.00619.x }}
* {{cite journal | vauthors = Simeone A, Acampora D, Mallamaci A, Stornaiuolo A, D'Apice MR, Nigro V, Boncinelli E | title = A vertebrate gene related to orthodenticle contains a homeodomain of the bicoid class and demarcates anterior neuroectoderm in the gastrulating mouse embryo | journal = The EMBO Journal | volume = 12 | issue = 7 | pages = 2735–47 | date = July 1993 | pmid = 8101484 | pmc = 413524 | doi = }}
* {{cite journal | vauthors = Nagao T, Leuzinger S, Acampora D, Simeone A, Finkelstein R, Reichert H, Furukubo-Tokunaga K | title = Developmental rescue of Drosophila cephalic defects by the human Otx genes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 7 | pages = 3737–42 | date = March 1998 | pmid = 9520436 | pmc = 19906 | doi = 10.1073/pnas.95.7.3737 | bibcode = 1998PNAS...95.3737N }}
* {{cite journal | vauthors = Bobola N, Briata P, Ilengo C, Rosatto N, Craft C, Corte G, Ravazzolo R | title = OTX2 homeodomain protein binds a DNA element necessary for interphotoreceptor retinoid binding protein gene expression | journal = Mechanisms of Development | volume = 82 | issue = 1-2 | pages = 165–9 | date = April 1999 | pmid = 10354480 | doi = 10.1016/S0925-4773(98)00162-2 }}
* {{cite journal | vauthors = Fong SL, Fong WB | title = Elements regulating the transcription of human interstitial retinoid-binding protein (IRBP) gene in cultured retinoblastoma cells | journal = Current Eye Research | volume = 18 | issue = 4 | pages = 283–91 | date = April 1999 | pmid = 10372988 | doi = 10.1076/ceyr.18.4.283.5360 }}
* {{cite journal | vauthors = Nakano T, Murata T, Matsuo I, Aizawa S | title = OTX2 directly interacts with LIM1 and HNF-3beta | journal = Biochemical and Biophysical Research Communications | volume = 267 | issue = 1 | pages = 64–70 | date = January 2000 | pmid = 10623575 | doi = 10.1006/bbrc.1999.1872 }}
* {{cite journal | vauthors = Takeda K, Yokoyama S, ((Yasumoto Ki)), Saito H, Udono T, Takahashi K, Shibahara S | title = OTX2 regulates expression of DOPAchrome tautomerase in human retinal pigment epithelium | journal = Biochemical and Biophysical Research Communications | volume = 300 | issue = 4 | pages = 908–14 | date = January 2003 | pmid = 12559959 | doi = 10.1016/S0006-291X(02)02934-0 }}
* {{cite journal | vauthors = Martínez-Morales JR, Dolez V, Rodrigo I, Zaccarini R, Leconte L, Bovolenta P, Saule S | title = OTX2 activates the molecular network underlying retina pigment epithelium differentiation | journal = The Journal of Biological Chemistry | volume = 278 | issue = 24 | pages = 21721–31 | date = June 2003 | pmid = 12663655 | doi = 10.1074/jbc.M301708200 }}
* {{cite journal | vauthors = Puelles E, Annino A, Tuorto F, Usiello A, Acampora D, Czerny T, Brodski C, Ang SL, Wurst W, Simeone A | title = Otx2 regulates the extent, identity and fate of neuronal progenitor domains in the ventral midbrain | journal = Development | volume = 131 | issue = 9 | pages = 2037–48 | date = May 2004 | pmid = 15105370 | doi = 10.1242/dev.01107 }}
* {{cite journal | vauthors = Boon K, Eberhart CG, Riggins GJ | title = Genomic amplification of orthodenticle homologue 2 in medulloblastomas | journal = Cancer Research | volume = 65 | issue = 3 | pages = 703–7 | date = February 2005 | pmid = 15705863 | doi =  }}
* {{cite journal | vauthors = Di C, Liao S, Adamson DC, Parrett TJ, Broderick DK, Shi Q, Lengauer C, Cummins JM, Velculescu VE, Fults DW, McLendon RE, Bigner DD, Yan H | title = Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid | journal = Cancer Research | volume = 65 | issue = 3 | pages = 919–24 | date = February 2005 | pmid = 15705891 | doi =  }}
* {{cite journal | vauthors = Ragge NK, Brown AG, Poloschek CM, Lorenz B, Henderson RA, Clarke MP, Russell-Eggitt I, Fielder A, Gerrelli D, Martinez-Barbera JP, Ruddle P, Hurst J, Collin JR, Salt A, Cooper ST, Thompson PJ, Sisodiya SM, Williamson KA, Fitzpatrick DR, van Heyningen V, Hanson IM | title = Heterozygous mutations of OTX2 cause severe ocular malformations | journal = American Journal of Human Genetics | volume = 76 | issue = 6 | pages = 1008–22 | date = June 2005 | pmid = 15846561 | pmc = 1196439 | doi = 10.1086/430721 }}
* {{cite journal | vauthors = Brunet I, Weinl C, Piper M, Trembleau A, Volovitch M, Harris W, Prochiantz A, Holt C | title = The transcription factor Engrailed-2 guides retinal axons | journal = Nature | volume = 438 | issue = 7064 | pages = 94–8 | date = November 2005 | pmid = 16267555 | doi = 10.1038/nature04110 | bibcode = 2005Natur.438...94B | pmc = 3785142 }}
* {{cite journal | vauthors = Chatelain G, Fossat N, Brun G, Lamonerie T | title = Molecular dissection reveals decreased activity and not dominant negative effect in human OTX2 mutants | journal = Journal of Molecular Medicine | volume = 84 | issue = 7 | pages = 604–15 | date = July 2006 | pmid = 16607563 | doi = 10.1007/s00109-006-0048-2 }}
* {{cite journal | vauthors = Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY | title = A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration | journal = Cell | volume = 125 | issue = 4 | pages = 801–14 | date = May 2006 | pmid = 16713569 | doi = 10.1016/j.cell.2006.03.032 }}
* {{cite journal | vauthors = Heimbucher T, Murko C, Bajoghli B, Aghaallaei N, Huber A, Stebegg R, Eberhard D, Fink M, Simeone A, Czerny T | title = Gbx2 and Otx2 interact with the WD40 domain of Groucho/Tle corepressors | journal = Molecular and Cellular Biology | volume = 27 | issue = 1 | pages = 340–51 | date = January 2007 | pmid = 17060451 | pmc = 1800652 | doi = 10.1128/MCB.00811-06 }}
{{refend}}
{{refend}}


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* {{MeshName|OTX2+protein,+human}}
* {{MeshName|OTX2+protein,+human}}


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{{PDB Gallery|geneid=5015}}
{{Transcription factors|g3}}


{{protein-stub}}
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{{Transcription factors}}
[[Category:Transcription factors]]
[[Category:Transcription factors]]
{{WikiDoc Sources}}

Latest revision as of 06:27, 10 January 2019

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Wikidata
View/Edit Human

Homeobox protein OTX2 is a protein that in humans is encoded by the OTX2 gene.[1][2]

Function

This gene encodes a member of the bicoid sub-family of homeodomain-containing transcription factors. The encoded protein acts as a transcription factor and may play a role in brain and sensory organ development. A similar protein in mice is required for proper forebrain development. Two transcript variants encoding distinct isoforms have been identified for this gene. Other alternative splice variants may exist, but their full length sequences have not been determined.[2]

Otx2 is a group of homeobox genes that are typically described as a head organizer in the primitive streak stage of embryonic development. Otx2, which is an encoded protein that plays the role of a transcription factor, has also been shown to be involved in the regional patterning of the midbrain and forebrain. This group of genes demonstrates later in progression to have an influence on the formation of the sensory organs, pituitary gland, pineal gland, inner ear, eye and optic nerve. Otx2 not only has a prominent role in developing this area but also aids in ensuring that the retina and brain stay intact. This group of genes has a huge role in development and if it is expressed incorrectly it can have detrimental effects on the fetus. Otx2 mutations have also been associated with seizures, developmental delays, short stature, structural abnormalities of the pituitary gland, and an early onset of degeneration of the retina. A “knockout” model on the group of Otx2 genes has been performed to see what effects it would have on the adult retina. It was found that without the Otx2 gene expression there was slow degeneration of photoreceptor cells in this area. Thus, proving that the homeobox genes of Otx2 are essential in forming a viable embryo.

Clinical significance

Otx2 is expressed in the brain, ear, nose and eye, and in the case of mutations; it can lead to significant developmental abnormalities and disorders. Mutations in OTX2 can cause eye disorders including anophthalmia and microphthalmia.[3] Apart from anophthalmia and microphthalmia, other abnormalities such as aplasia of the optic nerve, hypoplasia of the optic chiasm and dysplastic optic globes have also been observed. Other defects that occur due to a mutation of the Otx2 gene include pituitary abnormalities and mental retardation. Abnormal pituitary structure and/or function seem to be the most common feature associated with Otx2 mutations.[4]

Otx2 also regulates two other genes, Lhx1 and Dkk1 that also play a role in head morphogenesis.[5] Otx2 is required during early formation of the embryo to initiate the movement of cells towards the anterior region and establish the anterior visceral endoderm. In the absence of Otx2, this movement can be impeded, which can be overcome by the expression of Dkk1, but it does not prevent the embryo from developing head truncation defects. The absence of Otx2 and the enhanced expression of Lhx1 can also lead to severe head truncation.

It has been shown that if Otx2 is over expressed it can lead to childhood malignant brain tumors called medulloblastomas.

Duplication of OTX2 is involved in the pathogenesis of Hemifacial Microsomia .[6]

In the mouse, the lack of Otx2 inhibits the development of the head. These 'knockout' mice that fail to form the head have gastrulation defects and die at midgestation with severe brain anomalies.

Role of Otx2 in Visual Plasticity

Recent research has identified the homeoprotein Otx2 as a possible molecular ‘messenger’ that is necessary for experience-driven visual plasticity during the critical period.[7] Initially involved in embryonic head formation, Otx2 is re-expressed during the critical period of rats (>P23) and regulates the maturation of parvalbumin-expressing GABAergic interneurons (PV-cells), which control the onset of critical period plasticity.[8] Dark-rearing from birth and binocular enucleation of rats resulted in decreased expression of PV-cells and Otx2, which suggests that these proteins are visually experience-driven.[8] Otx2 loss-of-function experiments delayed ocular dominance plasticity by impairing the development of PV-cells.[8] Research into Otx2 and visual plasticity during the critical period is of particular interest to the study of developmental abnormalities such as amblyopia. More research must be conducted to determine if Otx2 could be utilized for therapeutic recovery of visual plasticity to aid some amblyopic patients.

References

  1. ↑ Kastury K, Druck T, Huebner K, Barletta C, Acampora D, Simeone A, Faiella A, Boncinelli E (July 1994). "Chromosome locations of human EMX and OTX genes". Genomics. 22 (1): 41–5. doi:10.1006/geno.1994.1343. PMID 7959790.
  2. ↑ 2.0 2.1 "Entrez Gene: OTX2 orthodenticle homeobox 2".
  3. ↑ Verma AS, Fitzpatrick DR (November 2007). "Anophthalmia and microphthalmia". Orphanet Journal of Rare Diseases. 2: 47. doi:10.1186/1750-1172-2-47. PMC 2246098. PMID 18039390.
  4. ↑ Schilter KF, Schneider A, Bardakjian T, Soucy JF, Tyler RC, Reis LM, Semina EV (February 2011). "OTX2 microphthalmia syndrome: four novel mutations and delineation of a phenotype". Clinical Genetics. 79 (2): 158–68. doi:10.1111/j.1399-0004.2010.01450.x. PMC 3017659. PMID 20486942.
  5. ↑ Ip CK, Fossat N, Jones V, Lamonerie T, Tam PP (October 2014). "Head formation: OTX2 regulates Dkk1 and Lhx1 activity in the anterior mesendoderm". Development. 141 (20): 3859–67. doi:10.1242/dev.114900. PMID 25231759.
  6. ↑ Zielinski D, Markus B, Sheikh M, Gymrek M, Chu C, Zaks M, Srinivasan B, Hoffman JD, Aizenbud D, Erlich Y (2014). "OTX2 duplication is implicated in hemifacial microsomia". PLoS One. 9 (5): e96788. Bibcode:2014PLoSO...996788Z. doi:10.1371/journal.pone.0096788. PMC 4016008. PMID 24816892.
  7. ↑ Sugiyama S, Prochiantz A, Hensch TK (April 2009). "From brain formation to plasticity: insights on Otx2 homeoprotein". Development, Growth & Differentiation. 51 (3): 369–77. doi:10.1111/j.1440-169X.2009.01093.x. PMID 19298552.
  8. ↑ 8.0 8.1 8.2 Sugiyama S, Di Nardo AA, Aizawa S, Matsuo I, Volovitch M, Prochiantz A, Hensch TK (August 2008). "Experience-dependent transfer of Otx2 homeoprotein into the visual cortex activates postnatal plasticity". Cell. 134 (3): 508–20. doi:10.1016/j.cell.2008.05.054. PMID 18692473.

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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