Review
The homeobox gene Otx2 in development and disease

https://doi.org/10.1016/j.exer.2013.03.007Get rights and content

Highlights

  • The homeobox gene Otx2 is essential for forebrain and craniofacial development.

  • In the eye, Otx2 is crucial for photoreceptors formation and maintenance.

  • In the visual cortex, the homeoprotein Otx2 appears to modulate postnatal plasticity.

  • In human, OTX2 mutations are associated with microphthalmia and brain abnormalities.

  • Several studies have pointed out an oncogenic role for OTX2 in medulloblastoma.

Abstract

The Otx2 gene encodes a transcription factor essential for the normal development of brain, cerebellum, pineal gland, and eye. In the retina, Otx2 has essential functions from early embryogenesis to adulthood. As soon as the optic vesicle is formed, the gene is required for retinal pigment epithelium specification. Otx2 is also a key regulator of photoreceptor genesis and differentiation, and is required after birth for bipolar cells terminal maturation. Otx2 expression is maintained in the differentiated retina wherein the gene is critical for the outer retina maintenance. In the visual cortex, the gene modulates the neuronal plasticity through a paracrine mechanism. OTX2 heterozygous mutations in humans have been linked to severe ocular malformations associated with brain abnormalities and pituitary dysfunction. Recent studies have also established the OTX2 gene as an oncogene for medulloblastoma, a malignant brain tumour originating in the cerebellum.

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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