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Gene Review

Otx2  -  orthodenticle homolog 2

Mus musculus

Synonyms: E130306E05Rik, Homeobox protein OTX2, Orthodenticle homolog 2, Otx-2
 
 
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Disease relevance of Otx2

  • In order to study this, we have perturbed the 3' UTR of Otx2 by inserting a small fragment of DNA from the lambda phage [1].
  • We have replaced part of the mouse homeogene Otx2 coding region with the E. coli lacZ coding sequence, thus creating a null allele of Otx2 [2].
  • Here we report that in the embryonic mouse eye Otx2, a paired homeodomain transcription factor, was found in retinal pigment epithelial cells and a restricted subset of retinal neurons, including ganglion cells [3].
 

High impact information on Otx2

  • Here we investigate whether the caudal limit of Otx2 expression is instrumental in positioning the isthmic organizer and in specifying midbrain versus hindbrain fate, by ectopically expressing Otx2 in the presumptive anterior hindbrain using a knock-in strategy into the En1 locus [4].
  • 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 [4].
  • The homeobox gene Otx2 is expressed in the anterior neural tube with a sharp limit at the midbrain/hindbrain junction (the isthmic organizer) [4].
  • In mice, Otx2 is expressed in the forebrain and midbrain and Gbx2 is expressed in the anterior hindbrain, with a shared border at the level of the MHB organizer [5].
  • Here we show that, in Gbx2-/- mutants, the earliest phenotype is a posterior expansion of the Otx2 domain during early somite stages [5].
 

Biological context of Otx2

 

Anatomical context of Otx2

 

Associations of Otx2 with chemical compounds

 

Regulatory relationships of Otx2

  • However, in the absence of Gbx2, FGF8 can nevertheless repress Otx2 expression in midbrain explants [18].
  • To achieve this, Otx2 was inactivated by Cre recombinase under the transcriptional control of En1 [12].
  • We examined whether Gbx2 is required after embryonic day 9 (E9) to repress Otx2 in the cerebellar anlage and position the midbrain/hindbrain organizer [19].
  • These data suggest that Otx3/Dmbx1 represses Otx2-mediated transcription in the developing brain [20].
  • In addition, transient expression of Otx2 in COS7 cells is able to dramatically enhance the transcriptional activity of the NCAM promoter [21].
 

Other interactions of Otx2

  • The Otx1 expression domain is similar to that of Otx2, but contained within it [9].
  • More strikingly, Fgf8b expression in more rostral brain regions appears to transform the midbrain and caudal forebrain into an anterior hindbrain fate through expansion of the Gbx2 domain and repression of Otx2 as early as the 7-somite stage [22].
  • Lack of Otx2 in the ventrolateral and posterior midbrain results in a dorsal expansion of Shh expression and in a dorsal and anterior rotation of the midbrain-hindbrain boundary and Fgf8 expression [12].
  • By contrast, Otx2 and Pax6 expression was not affected in Lmx1b(-/-) embryos [23].
  • Lhx5 expression is detected in the most anterior portion of the neural tube at the headfold stage, overlapping partially with Otx2 expression domain [24].
  • Lack of Otx2 in the VM specifically affects the proliferation of Sox2+ mesDA progenitors and causes their premature post-mitotic transition [25].
 

Analytical, diagnostic and therapeutic context of Otx2

  • Sequence analysis of the Otx2-3' UTR revealed a 140 bp long element that is present only in vertebrate Otx2 genes and conserved in identity by over 80% [1].
  • As shown by immunoblotting, Otx2 transfection affects the expression of a variety of cell and substratum adhesion molecules, rendering the cells a favourable substratum in neurite outgrowth assays [26].
  • Furthermore, our results indicate that the cells forming the HH20 constriction (coinciding with the caudal Otx2 limit) are the progeny of those located at the caudal Otx2 limit at stage HH10 (within the mesencephalic vesicle) [27].
  • Combined analysis of the relative abundance of Otx2 mRNA isoforms in representative tissues and in situ hybridization studies revealed distinct spatial and temporal, although partially overlapping, expression patterns of the mRNA isoforms [28].
  • We demonstrate that electroporation of dsRNA directed against Otx2 or Foxa2 into postimplantation mouse embryos results in specific knock down of the expression of the respective endogenous genes in a region- and germ-layer specific manner [29].

References

  1. Forebrain and midbrain development requires epiblast-restricted Otx2 translational control mediated by its 3' UTR. Boyl, P.P., Signore, M., Acampora, D., Martinez-Barbera, J.P., Ilengo, C., Annino, A., Corte, G., Simeone, A. Development (2001) [Pubmed]
  2. Forebrain and midbrain regions are deleted in Otx2-/- mutants due to a defective anterior neuroectoderm specification during gastrulation. Acampora, D., Mazan, S., Lallemand, Y., Avantaggiato, V., Maury, M., Simeone, A., Brûlet, P. Development (1995) [Pubmed]
  3. The subcellular localization of Otx2 is cell-type specific and developmentally regulated in the mouse retina. Baas, D., Bumsted, K.M., Martinez, J.A., Vaccarino, F.M., Wikler, K.C., Barnstable, C.J. Brain Res. Mol. Brain Res. (2000) [Pubmed]
  4. The caudal limit of Otx2 expression positions the isthmic organizer. Broccoli, V., Boncinelli, E., Wurst, W. Nature (1999) [Pubmed]
  5. A role for Gbx2 in repression of Otx2 and positioning the mid/hindbrain organizer. Millet, S., Campbell, K., Epstein, D.J., Losos, K., Harris, E., Joyner, A.L. Nature (1999) [Pubmed]
  6. Otx genes are required for tissue specification in the developing eye. Martinez-Morales, J.R., Signore, M., Acampora, D., Simeone, A., Bovolenta, P. Development (2001) [Pubmed]
  7. Cell autonomous and non-cell autonomous functions of Otx2 in patterning the rostral brain. Rhinn, M., Dierich, A., Le Meur, M., Ang, S. Development (1999) [Pubmed]
  8. Identification, tissue expression, and functional characterization of Otx3, a novel member of the Otx family. Zhang, Y., Miki, T., Iwanaga, T., Koseki, Y., Okuno, M., Sunaga, Y., Ozaki, N., Yano, H., Koseki, H., Seino, S. J. Biol. Chem. (2002) [Pubmed]
  9. Nested expression domains of four homeobox genes in developing rostral brain. Simeone, A., Acampora, D., Gulisano, M., Stornaiuolo, A., Boncinelli, E. Nature (1992) [Pubmed]
  10. Sequential roles for Otx2 in visceral endoderm and neuroectoderm for forebrain and midbrain induction and specification. Rhinn, M., Dierich, A., Shawlot, W., Behringer, R.R., Le Meur, M., Ang, S.L. Development (1998) [Pubmed]
  11. Genetic control of brain morphogenesis through Otx gene dosage requirement. Acampora, D., Avantaggiato, V., Tuorto, F., Simeone, A. Development (1997) [Pubmed]
  12. Otx2 regulates the extent, identity and fate of neuronal progenitor domains in the ventral midbrain. Puelles, E., Annino, A., Tuorto, F., Usiello, A., Acampora, D., Czerny, T., Brodski, C., Ang, S.L., Wurst, W., Simeone, A. Development (2004) [Pubmed]
  13. Emx and Otx homeobox genes in the developing mouse brain. Boncinelli, E., Gulisano, M., Broccoli, V. J. Neurobiol. (1993) [Pubmed]
  14. Otx2 and Gbx2 are required for refinement and not induction of mid-hindbrain gene expression. Li, J.Y., Joyner, A.L. Development (2001) [Pubmed]
  15. Involvement of Pax6 and Otx2 in the forebrain-specific regulation of the vertebrate homeobox gene ANF/Hesx1. Spieler, D., Bäumer, N., Stebler, J., Köprunner, M., Reichman-Fried, M., Teichmann, U., Raz, E., Kessel, M., Wittler, L. Dev. Biol. (2004) [Pubmed]
  16. Retinoic acid induces a tissue-specific deletion in the expression domain of Otx2. Clotman, F., Van Maele-Fabry, G., Picard, J.J. Neurotoxicology and teratology. (1997) [Pubmed]
  17. The Otx2 homeoprotein regulates expression from the gonadotropin-releasing hormone proximal promoter. Kelley, C.G., Lavorgna, G., Clark, M.E., Boncinelli, E., Mellon, P.L. Mol. Endocrinol. (2000) [Pubmed]
  18. EN and GBX2 play essential roles downstream of FGF8 in patterning the mouse mid/hindbrain region. Liu, A., Joyner, A.L. Development (2001) [Pubmed]
  19. Changing requirements for Gbx2 in development of the cerebellum and maintenance of the mid/hindbrain organizer. Li, J.Y., Lao, Z., Joyner, A.L. Neuron (2002) [Pubmed]
  20. Functional analysis of transcriptional repressor Otx3/Dmbx1. Kimura, K., Miki, T., Shibasaki, T., Zhang, Y., Ogawa, M., Saisho, H., Okuno, M., Iwanaga, T., Seino, S. FEBS Lett. (2005) [Pubmed]
  21. The mouse homeodomain protein OTX2 regulates NCAM promoter activity. Nguyen Ba-Charvet, K.T., von Boxberg, Y., Godement, P. Brain Res. Mol. Brain Res. (1999) [Pubmed]
  22. FGF8 can activate Gbx2 and transform regions of the rostral mouse brain into a hindbrain fate. Liu, A., Losos, K., Joyner, A.L. Development (1999) [Pubmed]
  23. Lmx1b is essential for Fgf8 and Wnt1 expression in the isthmic organizer during tectum and cerebellum development in mice. Guo, C., Qiu, H.Y., Huang, Y., Chen, H., Yang, R.Q., Chen, S.D., Johnson, R.L., Chen, Z.F., Ding, Y.Q. Development (2007) [Pubmed]
  24. Expression of murine Lhx5 suggests a role in specifying the forebrain. Sheng, H.Z., Bertuzzi, S., Chiang, C., Shawlot, W., Taira, M., Dawid, I., Westphal, H. Dev. Dyn. (1997) [Pubmed]
  25. Anterior-posterior graded response to Otx2 controls proliferation and differentiation of dopaminergic progenitors in the ventral mesencephalon. Omodei, D., Acampora, D., Mancuso, P., Prakash, N., Di Giovannantonio, L.G., Wurst, W., Simeone, A. Development (2008) [Pubmed]
  26. A potential role for the OTX2 homeoprotein in creating early 'highways' for axon extension in the rostral brain. Nguyen Ba-Charvet, K.T., von Boxberg, Y., Guazzi, S., Boncinelli, E., Godement, P. Development (1998) [Pubmed]
  27. 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. Millet, S., Bloch-Gallego, E., Simeone, A., Alvarado-Mallart, R.M. Development (1996) [Pubmed]
  28. New Otx2 mRNA isoforms expressed in the mouse brain. Courtois, V., Chatelain, G., Han, Z.Y., Le Novère, N., Brun, G., Lamonerie, T. J. Neurochem. (2003) [Pubmed]
  29. Spatial and temporal 'knock down' of gene expression by electroporation of double-stranded RNA and morpholinos into early postimplantation mouse embryos. Mellitzer, G., Hallonet, M., Chen, L., Ang, S.L. Mech. Dev. (2002) [Pubmed]
 
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