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.
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.
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. 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.
Otx2 also regulates two other genes, Lhx1 and Dkk1 that also play a role in head morphogenesis. 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.
Recent research has identified the homeoprotein Otx2 as a possible molecular ‘messenger’ that is necessary for experience-driven visual plasticity during the critical period. 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 periodplasticity. 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. Otx2 loss-of-function experiments delayed ocular dominance plasticity by impairing the development of PV-cells. 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.
^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. PMID25231759.
^ abcSugiyama 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. PMID18692473.
Millet S, Bloch-Gallego E, Simeone A, Alvarado-Mallart RM (December 1996). "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". Development. 122 (12): 3785–97. PMID9012500.
Kimura C, Takeda N, Suzuki M, Oshimura M, Aizawa S, Matsuo I (October 1997). "Cis-acting elements conserved between mouse and pufferfish Otx2 genes govern the expression in mesencephalic neural crest cells". Development. 124 (20): 3929–41. PMID9374391.
Gat-Yablonski G (September 2011). "Brain development is a multi-level regulated process--the case of the OTX2 gene". Pediatric Endocrinology Reviews. 9 (1): 422–30. PMID22783640.
Bobola N, Briata P, Ilengo C, Rosatto N, Craft C, Corte G, Ravazzolo R (April 1999). "OTX2 homeodomain protein binds a DNA element necessary for interphotoreceptor retinoid binding protein gene expression". Mechanisms of Development. 82 (1–2): 165–9. doi:10.1016/S0925-4773(98)00162-2. PMID10354480.
Fong SL, Fong WB (April 1999). "Elements regulating the transcription of human interstitial retinoid-binding protein (IRBP) gene in cultured retinoblastoma cells". Current Eye Research. 18 (4): 283–91. doi:10.1076/ceyr.18.4.283.5360. PMID10372988.
Nakano T, Murata T, Matsuo I, Aizawa S (January 2000). "OTX2 directly interacts with LIM1 and HNF-3beta". Biochemical and Biophysical Research Communications. 267 (1): 64–70. doi:10.1006/bbrc.1999.1872. PMID10623575.
Takeda K, Yokoyama S, Yasumoto Ki, Saito H, Udono T, Takahashi K, Shibahara S (January 2003). "OTX2 regulates expression of DOPAchrome tautomerase in human retinal pigment epithelium". Biochemical and Biophysical Research Communications. 300 (4): 908–14. doi:10.1016/S0006-291X(02)02934-0. PMID12559959.
Martínez-Morales JR, Dolez V, Rodrigo I, Zaccarini R, Leconte L, Bovolenta P, Saule S (June 2003). "OTX2 activates the molecular network underlying retina pigment epithelium differentiation". The Journal of Biological Chemistry. 278 (24): 21721–31. doi:10.1074/jbc.M301708200. PMID12663655.
Puelles E, Annino A, Tuorto F, Usiello A, Acampora D, Czerny T, Brodski C, Ang SL, Wurst W, Simeone A (May 2004). "Otx2 regulates the extent, identity and fate of neuronal progenitor domains in the ventral midbrain". Development. 131 (9): 2037–48. doi:10.1242/dev.01107. PMID15105370.
Boon K, Eberhart CG, Riggins GJ (February 2005). "Genomic amplification of orthodenticle homologue 2 in medulloblastomas". Cancer Research. 65 (3): 703–7. PMID15705863.
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 (February 2005). "Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid". Cancer Research. 65 (3): 919–24. PMID15705891.
Chatelain G, Fossat N, Brun G, Lamonerie T (July 2006). "Molecular dissection reveals decreased activity and not dominant negative effect in human OTX2 mutants". Journal of Molecular Medicine. 84 (7): 604–15. doi:10.1007/s00109-006-0048-2. PMID16607563.
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 (May 2006). "A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration". Cell. 125 (4): 801–14. doi:10.1016/j.cell.2006.03.032. PMID16713569.