Genomes and Genes
otx transcription factors
Summary: A family of VERTEBRATE homeodomain proteins that share homology with orthodenticle protein, Drosophila. They regulate GENETIC TRANSCRIPTION and play an important role in EMBRYONIC DEVELOPMENT of the BRAIN.
- Wurst W, Bally Cuif L. Neural plate patterning: upstream and downstream of the isthmic organizer. Nat Rev Neurosci. 2001;2:99-108 pubmed..Here we review our current knowledge on the identity, localization and maintenance of the isthmic organizer, as well as on the molecular cascades that underlie the activity of this organizing centre...
- Simeone A, Puelles E, Acampora D. The Otx family. Curr Opin Genet Dev. 2002;12:409-15 pubmed
- Acampora D, Annino A, Puelles E, Alfano I, Tuorto F, Simeone A. OTX1 compensates for OTX2 requirement in regionalisation of anterior neuroectoderm. Gene Expr Patterns. 2003;3:497-501 pubmed..Patterning and regionalisation of forebrain and midbrain were unaffected as revealed by the expression of diagnostic genes which are highly sensitive to reduction of OTX proteins, such as Fgf8, Pax2 and Gbx2. ..
- Chung C, Licznerski P, Alavian K, Simeone A, Lin Z, Martin E, et al. The transcription factor orthodenticle homeobox 2 influences axonal projections and vulnerability of midbrain dopaminergic neurons. Brain. 2010;133:2022-31 pubmed publisher..These results show that orthodenticle homeobox 2 is important for establishing subgroup phenotypes of post-mitotic midbrain dopaminergic neurons and may alter neuronal vulnerability. ..
- Tian E, Kimura C, Takeda N, Aizawa S, Matsuo I. Otx2 is required to respond to signals from anterior neural ridge for forebrain specification. Dev Biol. 2002;242:204-23 pubmed..These results further suggest that Otx2 dosage may be crucial in the neural plate with respect to response to inductive signals primarily from the ANR for forebrain specification. ..
- Oda Ishii I, Bertrand V, Matsuo I, Lemaire P, Saiga H. Making very similar embryos with divergent genomes: conservation of regulatory mechanisms of Otx between the ascidians Halocynthia roretzi and Ciona intestinalis. Development. 2005;132:1663-74 pubmed..The regulation of Otx in the anterior endoderm by Lhx and Fox factors may even be conserved with vertebrates. ..
- Acampora D, Boyl P, Signore M, Martinez Barbera J, Ilengo C, Puelles E, et al. OTD/OTX2 functional equivalence depends on 5' and 3' UTR-mediated control of Otx2 mRNA for nucleo-cytoplasmic export and epiblast-restricted translation. Development. 2001;128:4801-13 pubmed..These data provide novel in vivo evidence supporting the concept that during evolution pre-existing gene functions have been recruited into new developmental pathways by modifying their regulatory control. ..
- Agoston Z, Schulte D. Meis2 competes with the Groucho co-repressor Tle4 for binding to Otx2 and specifies tectal fate without induction of a secondary midbrain-hindbrain boundary organizer. Development. 2009;136:3311-22 pubmed publisher..Controlled formation of Meis2-containing higher order protein complexes might thus serve as a general mechanism to achieve subdivision of the anterior neuroectoderm into distinct functional units during embryogenesis. ..
- Waters S, Wilson C, Lewandoski M. Cloning and embryonic expression analysis of the mouse Gbx1 gene. Gene Expr Patterns. 2003;3:313-7 pubmed..Finally, we demonstrate that neither Gbx1 nor Gbx2 require FGF8 for expression during gastrulation, contrary to previous published reports. ..
- Danno H, Michiue T, Hitachi K, Yukita A, Ishiura S, Asashima M. Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression. Proc Natl Acad Sci U S A. 2008;105:5408-13 pubmed publisher..These results demonstrate that the direct interaction and interdependence between the Otx2 and Sox2 proteins coordinate Rax expression in eye development, providing molecular linkages among the genes responsible for ocular malformation...
- Boon K, Eberhart C, Riggins G. Genomic amplification of orthodenticle homologue 2 in medulloblastomas. Cancer Res. 2005;65:703-7 pubmed..OTX2 functions to specify the fate of neuroectoderm in various regions of the developing brain. This developmental role is consistent with the evidence suggesting that OTX2 is a medulloblastoma oncogene. ..
- Gogoi R, Schubert F, Martinez Barbera J, Acampora D, Simeone A, Lumsden A. The paired-type homeobox gene Dmbx1 marks the midbrain and pretectum. Mech Dev. 2002;114:213-7 pubmed..At later stages, Dmbx1 is expressed in dynamic domains of the hindbrain and spinal cord. Additional sites of expression comprise stomodeal ectoderm and foregut endoderm, presomitic mesoderm, and the nasal pit. ..
- Sakami S, Hisatomi O, Sakakibara S, Liu J, Reh T, Tokunaga F. Downregulation of Otx2 in the dedifferentiated RPE cells of regenerating newt retina. Brain Res Dev Brain Res. 2005;155:49-59 pubmed..In contrast to RPE cell markers, CRALBP was expressed in both the pigmented and the de-pigmented layers. This observation implicates the appearance of Muller glial cells in an early phase of regenerating retina. ..
- Martinez Morales J, Signore M, Acampora D, Simeone A, Bovolenta P. Otx genes are required for tissue specification in the developing eye. Development. 2001;128:2019-30 pubmed
- Rath M, Morin F, Shi Q, Klein D, Møller M. Ontogenetic expression of the Otx2 and Crx homeobox genes in the retina of the rat. Exp Eye Res. 2007;85:65-73 pubmed..In this regard, these results provide an enhanced and expanded temporal and spatial framework for understanding the multiple roles of Otx2 and Crx in the developing and mature mammalian retina. ..
- Fujimoto W, Shiuchi T, Miki T, Minokoshi Y, Takahashi Y, Takeuchi A, et al. Dmbx1 is essential in agouti-related protein action. Proc Natl Acad Sci U S A. 2007;104:15514-9 pubmed..Thus, Dmbx1 is essential for various actions of agouti-related protein and plays a role in normal regulation of energy homeostasis and behavior. ..
- Hudson C, Lemaire P. Induction of anterior neural fates in the ascidian Ciona intestinalis. Mech Dev. 2001;100:189-203 pubmed..Our results, however, indicate that bFGF can only induce a subset of the responses of the endogenous inducer, suggesting that additional signals in the embryo are necessary to induce a fully patterned nervous system. ..
- Joyner A, Liu A, Millet S. Otx2, Gbx2 and Fgf8 interact to position and maintain a mid-hindbrain organizer. Curr Opin Cell Biol. 2000;12:736-41 pubmed..Recent experiments have shown that Otx2, Gbx2 and Fgf8 genes play a major role in the positioning and functioning of this organizing center...
- Broccoli V, Boncinelli E, Wurst W. The caudal limit of Otx2 expression positions the isthmic organizer. Nature. 1999;401:164-8 pubmed..These findings show that the caudal limit of Otx2 expression is sufficient for positioning the isthmic organizer and encoding caudal midbrain fate within the mid/hindbrain domain. ..
- Rhinn M, Dierich A, Le Meur M, Ang S. Cell autonomous and non-cell autonomous functions of Otx2 in patterning the rostral brain. Development. 1999;126:4295-304 pubmed..Altogether, this study demonstrates that Otx2 is an important regulator of brain patterning and morphogenesis, through its regulation of candidate target genes such as Rpx/Hesx1, Wnt1, R-cadherin and ephrin-A2. ..
- Adamson D, Shi Q, Wortham M, Northcott P, Di C, Duncan C, et al. OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas. Cancer Res. 2010;70:181-91 pubmed publisher..Mechanistic investigations revealed upregulation of MYC as a potential mechanism whereby OTX2 promotes tumor progression. Our findings define OTX2 as an important oncogenic driver in medulloblastoma...
- Acampora D, Avantaggiato V, Tuorto F, Barone P, Perera M, Choo D, et al. Differential transcriptional control as the major molecular event in generating Otx1-/- and Otx2-/- divergent phenotypes. Development. 1999;126:1417-26 pubmed
- Bunt J, de Haas T, Hasselt N, Zwijnenburg D, Koster J, Versteeg R, et al. Regulation of cell cycle genes and induction of senescence by overexpression of OTX2 in medulloblastoma cell lines. Mol Cancer Res. 2010;8:1344-57 pubmed publisher..Our data indicate that OTX2 directly induces a series of cell cycle genes but requires cooperating genes for an oncogenic acceleration of the cell cycle. ..
- Ohtoshi A, Behringer R. Neonatal lethality, dwarfism, and abnormal brain development in Dmbx1 mutant mice. Mol Cell Biol. 2004;24:7548-58 pubmed..These results demonstrate that Dmbx1 is required for postnatal survival, growth, and brain development. ..
- Rhinn M, Lun K, Luz M, Werner M, Brand M. Positioning of the midbrain-hindbrain boundary organizer through global posteriorization of the neuroectoderm mediated by Wnt8 signaling. Development. 2005;132:1261-72 pubmed..Our findings argue that graded Wnt8 activity mediates overall neuroectodermal posteriorization and thus determines the location of the MHB organizer. ..
- Castro L, Rasmussen S, Holland P, Holland N, Holland L. A Gbx homeobox gene in amphioxus: insights into ancestry of the ANTP class and evolution of the midbrain/hindbrain boundary. Dev Biol. 2006;295:40-51 pubmed
- Fossat N, Le Greneur C, Beby F, Vincent S, Godement P, Chatelain G, et al. A new GFP-tagged line reveals unexpected Otx2 protein localization in retinal photoreceptors. BMC Dev Biol. 2007;7:122 pubmed..This opens up the way to live imaging of a highly dynamic actor of brain development and can be adapted to any mutant background to probe for genetic interaction between Otx2 and the mutated gene. ..
- Sugiyama S, Di Nardo A, Aizawa S, Matsuo I, Volovitch M, Prochiantz A, et al. Experience-dependent transfer of Otx2 homeoprotein into the visual cortex activates postnatal plasticity. Cell. 2008;134:508-20 pubmed publisher..Thus, the experience-dependent transfer of a homeoprotein may establish the physiological milieu for postnatal plasticity of a neural circuit. ..
- Bunt J, Hasselt N, Zwijnenburg D, Hamdi M, Koster J, Versteeg R, et al. OTX2 directly activates cell cycle genes and inhibits differentiation in medulloblastoma cells. Int J Cancer. 2012;131:E21-32 pubmed publisher..These analyses provide more insight in the molecular network of OTX2, demonstrating that OTX2 is essential in medulloblastoma and directly drives proliferation by regulation of cell cycle genes. ..
- Iwafuchi Doi M, Matsuda K, Murakami K, Niwa H, Tesar P, Aruga J, et al. Transcriptional regulatory networks in epiblast cells and during anterior neural plate development as modeled in epiblast stem cells. Development. 2012;139:3926-37 pubmed publisher..The direct interaction of these factors with enhancers of Otx2, Hesx1 and Sox2 genes was demonstrated. Thus, a combination of regulatory processes that suppresses non-ANP lineages and promotes neural plate development determines the ANP...
- Kimura C, Yoshinaga K, Tian E, Suzuki M, Aizawa S, Matsuo I. Visceral endoderm mediates forebrain development by suppressing posteriorizing signals. Dev Biol. 2000;225:304-21 pubmed..These results suggest that distal visceral endoderm cells move to the future anterior side to generate a prospective forebrain territory indirectly, by preventing posteriorizing signals. ..
- Acampora D, Avantaggiato V, Tuorto F, Simeone A. Genetic control of brain morphogenesis through Otx gene dosage requirement. Development. 1997;124:3639-50 pubmed
- Kim D, Matsuda T, Cepko C. A core paired-type and POU homeodomain-containing transcription factor program drives retinal bipolar cell gene expression. J Neurosci. 2008;28:7748-64 pubmed publisher..The paired-type and POU homeodomain-containing TFs Otx2 and Brn2 together appear to play a common role in regulating gene expression in retinal bipolar cells. ..
- Dateki S, Fukami M, Sato N, Muroya K, Adachi M, Ogata T. OTX2 mutation in a patient with anophthalmia, short stature, and partial growth hormone deficiency: functional studies using the IRBP, HESX1, and POU1F1 promoters. J Clin Endocrinol Metab. 2008;93:3697-702 pubmed publisher..It is likely that the heterozygous severe OTX2 loss-of-function mutation caused GH deficiency and short stature, primarily because of decreased transactivation function for HESX1 and POU1F1. ..
- Sugiyama S, Prochiantz A, Hensch T. From brain formation to plasticity: insights on Otx2 homeoprotein. Dev Growth Differ. 2009;51:369-77 pubmed publisher..Here, we discuss recent data that are beginning to illuminate the physiological function of non-cell autonomous homeoproteins, as well as the restriction of their transfer to PV-cells in vivo. ..
- Mallamaci A, Di Blas E, Briata P, Boncinelli E, Corte G. OTX2 homeoprotein in the developing central nervous system and migratory cells of the olfactory area. Mech Dev. 1996;58:165-78 pubmed
- Broccoli V, Colombo E, Cossu G. Dmbx1 is a paired-box containing gene specifically expressed in the caudal most brain structures. Mech Dev. 2002;114:219-23 pubmed..Interestingly, Dmbx1 expression labels cerebellar granule progenitors at the onset of differentiation and spinal cord V0 interneurons. ..
- Rath M, Muñoz E, Ganguly S, Morin F, Shi Q, Klein D, et al. Expression of the Otx2 homeobox gene in the developing mammalian brain: embryonic and adult expression in the pineal gland. J Neurochem. 2006;97:556-66 pubmed
- Li J, Joyner A. Otx2 and Gbx2 are required for refinement and not induction of mid-hindbrain gene expression. Development. 2001;128:4979-91 pubmed..Furthermore, Otx2 and Gbx2 are required to suppress hindbrain and midbrain development, respectively, and thus allow establishment of the normal spatial domains of Fgf8 and other genes. ..
- Millet S, Campbell K, Epstein D, Losos K, Harris E, Joyner A. A role for Gbx2 in repression of Otx2 and positioning the mid/hindbrain organizer. Nature. 1999;401:161-4 pubmed..5-10. We propose that formation of a normal MHB organizer depends on a sharp Otx2 caudal border and that Gbx2 is required to position and sharpen this border. ..
- Nishida A, Furukawa A, Koike C, Tano Y, Aizawa S, Matsuo I, et al. Otx2 homeobox gene controls retinal photoreceptor cell fate and pineal gland development. Nat Neurosci. 2003;6:1255-63 pubmed..Thus, Otx2 is a key regulatory gene for the cell fate determination of retinal photoreceptor cells. Our results reveal the key molecular steps required for photoreceptor cell-fate determination and pinealocyte development. ..
- Koike C, Nishida A, Ueno S, Saito H, Sanuki R, Sato S, et al. Functional roles of Otx2 transcription factor in postnatal mouse retinal development. Mol Cell Biol. 2007;27:8318-29 pubmed..These data suggest that Otx2 plays a functional role in the maturation of retinal photoreceptor and bipolar cells. ..
- Adachi Y, Nagao T, Saiga H, Furukubo Tokunaga K. Cross-phylum regulatory potential of the ascidian Otx gene in brain development in Drosophila melanogaster. Dev Genes Evol. 2001;211:269-80 pubmed
- Zuber M, Gestri G, Viczian A, Barsacchi G, Harris W. Specification of the vertebrate eye by a network of eye field transcription factors. Development. 2003;130:5155-67 pubmed..We find striking similarities and differences to the network of homologous Drosophila genes that specify the eye imaginal disc, a finding that is consistent with the idea of a partial evolutionary conservation of eye formation. ..
- Bobola N, Briata P, Ilengo C, Rosatto N, Craft C, Corte G, et al. OTX2 homeodomain protein binds a DNA element necessary for interphotoreceptor retinoid binding protein gene expression. Mech Dev. 1999;82:165-9 pubmed..OTX2, as well as CRX, a homeodomain protein very similar to OTX2, activates the human IRBP promoter in co-transfection experiments. ..
- Suda Y, Matsuo I, Kuratani S, Aizawa S. Otx1 function overlaps with Otx2 in development of mouse forebrain and midbrain. Genes Cells. 1996;1:1031-44 pubmed..Otx1 and Otx2 play synergistic roles in the development of the forebrain and midbrain where both genes are expressed. ..
- Acampora D, Mazan S, Avantaggiato V, Barone P, Tuorto F, Lallemand Y, et al. Epilepsy and brain abnormalities in mice lacking the Otx1 gene. Nat Genet. 1996;14:218-22 pubmed..Our findings indicate that the Otx1 gene product is required for proper brain functions. ..
- Simeone A, Acampora D, Mallamaci A, Stornaiuolo A, D Apice M, Nigro V, et al. A vertebrate gene related to orthodenticle contains a homeodomain of the bicoid class and demarcates anterior neuroectoderm in the gastrulating mouse embryo. EMBO J. 1993;12:2735-47 pubmed..Its gene product contains a homeodomain of the bicoid class and is able to recognize and transactivate a bicoid target sequence. ..
- Omodei D, Acampora D, Mancuso P, Prakash N, Di Giovannantonio L, Wurst W, et al. Anterior-posterior graded response to Otx2 controls proliferation and differentiation of dopaminergic progenitors in the ventral mesencephalon. Development. 2008;135:3459-70 pubmed publisher..Thus, our data provide new insights into the mechanism of mesDA neuron specification and suggest Otx2 as a potential target for cell replacement-based therapeutic approaches in PD. ..
- Gamse J, Sive H. Early anteroposterior division of the presumptive neurectoderm in Xenopus. Mech Dev. 2001;104:21-36 pubmed..These data show that neural patterning occurs early in Xenopus and suggest a molecular basis for initiating this pattern. ..
- Puelles E, Acampora D, Gogoi R, Tuorto F, Papalia A, Guillemot F, et al. Otx2 controls identity and fate of glutamatergic progenitors of the thalamus by repressing GABAergic differentiation. J Neurosci. 2006;26:5955-64 pubmed..Our data also support the concept that proper assignment of identity and fate of neuronal precursors occurs through the suppression of alternative differentiation programs. ..
- de Haas T, Oussoren E, Grajkowska W, Perek Polnik M, Popovic M, Zadravec Zaletel L, et al. OTX1 and OTX2 expression correlates with the clinicopathologic classification of medulloblastomas. J Neuropathol Exp Neurol. 2006;65:176-86 pubmed..Combined with data from rodents, our results therefore suggest that both nodular/desmoplastic and at least part of the classic medulloblastomas originate from cells of the EGL, albeit from different regions. ..
- Fossat N, Courtois V, Chatelain G, Brun G, Lamonerie T. Alternative usage of Otx2 promoters during mouse development. Dev Dyn. 2005;233:154-60 pubmed..The third promoter, which shows no activity in embryonic stem cells and is moderately expressed during embryogenesis, is mostly used in specific areas derived from the rostral part of the neural tube. ..
- Di C, Liao S, Adamson D, Parrett T, Broderick D, Shi Q, et al. Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid. Cancer Res. 2005;65:919-24 pubmed..These observations suggest that OTX2 is essential for the pathogenesis of anaplastic medulloblastomas and that these tumors may be amenable to therapy with all-trans-retinoic acid. ..
- Takeda K, Yokoyama S, Yasumoto K, Saito H, Udono T, Takahashi K, et al. OTX2 regulates expression of DOPAchrome tautomerase in human retinal pigment epithelium. Biochem Biophys Res Commun. 2003;300:908-14 pubmed..Therefore, OTX2 may regulate RPE-specific target genes, such as DCT, thereby maintaining the homeostasis of RPE. ..
- Bellipanni G, Murakami T, Doerre O, Andermann P, Weinberg E. Expression of Otx homeodomain proteins induces cell aggregation in developing zebrafish embryos. Dev Biol. 2000;223:339-53 pubmed..These results suggest that promotion of cell adhesion or mediation of cell repulsion may be one of the normal functions of the Otx proteins in the establishment of the anterior brain. ..
- Esumi N, Kachi S, Hackler L, Masuda T, Yang Z, Campochiaro P, et al. BEST1 expression in the retinal pigment epithelium is modulated by OTX family members. Hum Mol Genet. 2009;18:128-41 pubmed publisher..These results demonstrate for the first time CRX expression in the RPE, and suggest that OTX2 and CRX may act as positive modulators of the BEST1 promoter in the RPE. ..
- Baas D, Bumsted K, Martinez J, Vaccarino F, Wikler K, Barnstable C. The subcellular localization of Otx2 is cell-type specific and developmentally regulated in the mouse retina. Brain Res Mol Brain Res. 2000;78:26-37 pubmed
- Tour E, Pillemer G, Gruenbaum Y, Fainsod A. Gbx2 interacts with Otx2 and patterns the anterior-posterior axis during gastrulation in Xenopus. Mech Dev. 2002;112:141-51 pubmed
- Terrinoni A, Pagani I, Zucchi I, Chiaravalli A, Serra V, Rovera F, et al. OTX1 expression in breast cancer is regulated by p53. Oncogene. 2011;30:3096-103 pubmed publisher..Wild-type p53 may regulate cellular differentiation by an alternative pathway controlling OTX1 signaling only in breast cancer cells and not in physiological conditions. ..