Homeobox protein OTX2 is a protein that in humans is encoded by the OTX2 gene. [5] [6]
Homeobox protein OTX2 is a protein that in humans is encoded by the OTX2 gene. [5] [6]
This gene encodes a member of the bicoid sub-family of homeodomain-containing transcription factors. The encoded protein acts as a transcription factor and plays 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. [6]
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 necessary for retina development, retina maturation, and fate determination of photoreceptors. In the mouse, studies have shown development of the retina is regulated in a cell type- and stage-specific manner by seven Otx2 cis-regulatory modules. Three of these cis-regulatory modules, O5, O7 and O9 indicate three distinct cellular expressions of Otx2. [7] A “knockin” mouse line was generated where Crx (Otx family homeoprotein) was replaced by Otx2 and vice versa to examine the functional substitutability. It was found that Crx and Otx2 cannot be substituted in photoreceptor development. High Otx2 levels induce photoreceptor cell fate but not bipolar cell fate. Low levels of Otx2 impair bipolar cell maturation and survival. [8] Studies in the chicken confirmed a functional role for Otx2 in the determination of photoreceptors. Otx2 also represses specific retinal fates (such as subtypes of retinal ganglion and horizontal cells) of sister cells to promote the specification of photoreceptors. [9]
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. [10] 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. [11]
Otx2 also regulates two other genes, Lhx1 and Dkk1 that also play a role in head morphogenesis. [12] 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 overexpressed, it can lead to childhood malignant brain tumors called medulloblastomas.
Duplication of OTX2 is involved in the pathogenesis of Hemifacial Microsomia.
In the mouse, the lack of Otx2 inhibits the development of the head. These 'knockout' mice that fail to form the head have gastrulation defects and die at midgestation with severe brain anomalies.
Recent research has identified the homeoprotein Otx2 as a possible molecular ‘messenger’ that is necessary for experience-driven visual plasticity during the critical period. [13] 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 period plasticity. [14] 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. [14] Otx2 loss-of-function experiments delayed ocular dominance plasticity by impairing the development of PV-cells. [14] 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.
Otx2 is a key regulator of the earliest stages of ES cell differentiation. [15] [16] The ectopic expression of Otx2 drives ES cells into differentiation, even in the presence of the LIF cytokine. At the molecular level, Otx2 induction partially compensates the gene expression changes induced by Nanog overexpression in the absence of LIF. [15]
The Otx2 gene is an important transcription factor in the formation of dopaminergic neurons in the Ventral tegmental Area (VTA), an area located in the midbrain. The VTA is involved in drug reinforcement, reward processing, and addiction in the adult. Ethanol consumption during embryogenesis, leads to a reduction in Otx2 mRNA in the central nervous system altering gene expression. This altering of gene expression in the central nervous system in utero may contribute to addiction behaviors as an adult. In order to detect if the reduction of Otx2 due to ethanol caused an increase in binge-drinking behaviors in adults, a lentiviral hairpin (sh)RNA was used to target Otx2 and reduce the levels of Otx2 expression in the VTA in mice. The mice were then administered ethanol. It was found that Otx2 may contribute to binge-like drinking through transcriptional changes in the VTA (Coles & Lasek, 2021.
Homeobox protein Hox-B7 is a protein that in humans is encoded by the HOXB7 gene.
Homeobox D10, also known as HOXD10, is a protein which in humans is encoded by the HOXD10 gene.
Homeobox protein Hox-B5 is a protein that in humans is encoded by the HOXB5 gene.
Homeobox protein Hox-C8 is a protein that in humans is encoded by the HOXC8 gene.
Homeobox protein DLX-5 is a protein that in humans is encoded by the distal-less homeobox 5 gene, or DLX5 gene. DLX5 is a member of the DLX gene family.
Homeobox protein Hox-B1 is a protein that in humans is encoded by the HOXB1 gene.
Homeobox protein Hox-B2 is a protein that in humans is encoded by the HOXB2 gene.
Homeobox protein Hox-B9 is a protein that in humans is encoded by the HOXB9 gene.
POU domain, class 4, transcription factor 1 (POU4F1) also known as brain-specific homeobox/POU domain protein 3A (BRN3A), homeobox/POU domain protein RDC-1 or Oct-T1 is a protein that in humans is encoded by the POU4F1 gene.
Homeobox protein Hox-C4 is a protein that in humans is encoded by the HOXC4 gene.
Homeobox protein Hox-C6 is a protein that in humans is encoded by the HOXC6 gene. Hox-C6 expression is highest in the fallopian tube and ovary. HoxC6 has been highly expressed in many types of cancers including prostate, breast, and esophageal squamous cell cancer.
Homeobox protein SIX3 is a protein that in humans is encoded by the SIX3 gene.
Homeobox protein Emx2 is a protein that in humans is encoded by the EMX2 gene.
Homeobox protein Hox-C5 is a protein that in humans is encoded by the HOXC5 gene.
Homeobox protein OTX1 is a protein that in humans is encoded by the OTX1 gene.
Homeobox protein DLX-2 is a protein that in humans is encoded by the DLX2 gene.
Homeobox protein EMX1 is a protein that in humans is encoded by the EMX1 gene. The transcribed EMX1 gene is a member of the EMX family of transcription factors. The EMX1 gene, along with its family members, are expressed in the developing cerebrum. EMX1 plays a role in specification of positional identity, the proliferation of neural stem cells, differentiation of layer-specific neuronal phenotypes and commitment to a neuronal or glial cell fate.
Homeobox protein GBX-2 is a protein that in humans is encoded by the GBX2 gene.
Orthodenticle (otd) is a homeobox gene found in Drosophila that regulates the development of anterior patterning, with particular involvement in the central nervous system function and eye development. It is located on the X chromosome. The gene is an ortholog of the human OTX1/OTX2 gene.
Retinal homeobox protein Rx also known as retina and anterior neural fold homeobox is a protein that in humans is encoded by the RAX gene. The RAX gene is located on chromosome 18 in humans, mice, and rats.
Coles, C., & Lasek, A. W. (2021). Binge-like ethanol drinking increases otx2, wnt1, and mdk gene expression in the ventral tegmental area of adult mice. Neuroscience Insights, 16, 263310552110098. https://doi.org/10.1177/26331055211009850 == External links ==
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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