ReviewThe homeobox gene Otx2 in development and disease
Section snippets
Structure
The OTX2 protein (Orthodenticle homeobox 2) is a homeodomain-containing transcription factor, which plays a critical role in forebrain and eye development. The OTX2 gene is located on human chromosome 14q22.3 and is organized into five exons of which the first two exons are noncoding. Alternative splicing results in two OTX2 mRNA transcripts encoding two isoforms: a full-length OTX2 protein containing 297 amino acids (NP_068374.1), and a shorter isoform, a 289 amino acid residues long protein (NP_758840.1
Otx2 is required for forebrain induction and specification
Together with Otx1 and the more distantly related Crx, Otx2 gene is a vertebrate ortholog to the Drosophila orthodenticle homeobox gene (Simeone et al., 1992). The Otx2 homeobox gene is one of the most important genes for forebrain induction and head formation in vertebrates. In mouse embryo, Otx2 is already transcribed from the embryonic morula stage, and in the murine blastula, the Otx2 expression is detected in the entire epiblast. During the gastrulation process, the expression becomes
OTX2 mutations are associated with blinding ocular defects and brain abnormalities
The major phenotype encountered in patients with heterozygous OTX2 mutations (Table 1) consists in severe ocular defects associated with brain malformations (Ragge et al., 2005) or pituitary abnormalities (Schilter et al., 2011). The OTX2 mutations described so far (Fig. 1) seem to be sparsely distributed throughout the protein, although a majority of them involves the last exon of the gene.
For the majority of the patients, the disease can be considered as a haploinsufficiency neuro-ocular
Future studies regarding Otx2 functions in the eye
To better understand the function of Otx2 during eye development and in post-natal life, it is critically needed to document the repertoire of genes controlled by this transcription factor at various stages. Several genetic mouse models have been engineered, all relying on floxed Otx2 alleles, that allow ablation of the gene in various spatial and temporal conditions. Among these, a model coined Otx2 self-knockout allows to perform full ablation of the gene in all cells where it is expressed,
Author contributions
Francis Beby: wrote the manuscript.
Thomas Lamonerie: wrote the manuscript.
Conflict of interest
None of the authors declare any conflict of interest.
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