Paired box protein Pax-6, also known as aniridia type II protein (AN2) or oculorhombin, is a protein that in humans is encoded by the PAX6 gene. [5]
Paired box protein Pax-6, also known as aniridia type II protein (AN2) or oculorhombin, is a protein that in humans is encoded by the PAX6 gene. [5]
PAX6 is a member of the Pax gene family which is responsible for carrying the genetic information that will encode the Pax-6 protein. It acts as a "master control" gene for the development of eyes and other sensory organs, certain neural and epidermal tissues as well as other homologous structures, usually derived from ectodermal tissues.[ citation needed ] However, it has been recognized that a suite of genes is necessary for eye development, and therefore the term of "master control" gene may be inaccurate. [6] Pax-6 is expressed as a transcription factor when neural ectoderm receives a combination of weak Sonic hedgehog (SHH) and strong TGF-Beta signaling gradients. Expression is first seen in the forebrain, hindbrain, head ectoderm and spinal cord followed by later expression in midbrain. This transcription factor is most noted for its use in the interspecifically induced expression of ectopic eyes and is of medical importance because heterozygous mutants produce a wide spectrum of ocular defects such as aniridia in humans. [7]
Pax6 serves as a regulator in the coordination and pattern formation required for differentiation and proliferation to successfully take place, ensuring that the processes of neurogenesis and oculogenesis are carried out successfully. As a transcription factor, Pax6 acts at the molecular level in the signaling and formation of the central nervous system. The characteristic paired DNA binding domain of Pax6 utilizes two DNA-binding domains, the paired domain (PD), and the paired-type homeodomain (HD). These domains function separately via utilization by Pax6 to carry out molecular signaling that regulates specific functions of Pax6. An example of this lies in HD's regulatory involvement in the formation of the lens and retina throughout oculogenesis contrasted by the molecular mechanisms of control exhibited on the patterns of neurogenesis in brain development by PD. The HD and PD domains act in close coordination, giving Pax6 its multifunctional nature in directing molecular signaling in formation of the CNS. Although many functions of Pax6 are known, the molecular mechanisms of these functions remain largely unresolved. [8] High-throughput studies uncovered many new target genes of the Pax6 transcription factors during lens development. [9] They include the transcriptional activator BCL9, recently identified, together with Pygo2, to be downstream effectors of Pax6 functions. [10]
PAX6 protein function is highly conserved across bilaterian species. For instance, mouse PAX6 can trigger eye development in Drosophila melanogaster. Additionally, mouse and human PAX6 have identical amino acid sequences. [11]
Genomic organisation of the PAX6 locus varies among species, including the number and distribution of exons, cis-regulatory elements, and transcription start sites, [12] [13] although most elements at the Vertebrata clade do line up with each other. [14] [15] The first work on genomic organisation was performed in quail, but the picture of the mouse locus is the most complete to date. This consists of 3 confirmed promoters (P0, P1, Pα), 16 exons, and at least 6 enhancers. The 16 confirmed exons are numbered 0 through 13 with the additions of exon α located between exons 4 and 5, and the alternatively spliced exon 5a. Each promoter is associated with its own proximal exon (exon 0 for P0, exon 1 for P1) resulting in transcripts which are alternatively spliced in the 5' un-translated region. [16] By convention, exon for orthologs from other species are named relative to the human/mouse numbering, as long as the organization is reasonably well-conserved. [15]
Of the four Drosophila Pax6 orthologues, it is thought that the eyeless (ey) and twin of eyeless (toy) gene products share functional homology with the vertebrate canonical Pax6 isoform, while the eyegone (eyg) and twin of eyegone (toe) gene products share functional homology with the vertebrate Pax6(5a) isoform. Eyeless and eyegone were named for their respective mutant phenotypes. These paralogs also play a role in the development in the entire eye-antennal disc, and consequently in head formation. [17] toy positively regulates ey expression. [18]
The vertebrate PAX6 locus encodes at least three different protein isoforms, these being the canonical PAX6, PAX6(5a), and PAX6(ΔPD). The canonical PAX6 protein contains an N-terminal paired domain, connected by a linker region to a paired-type homeodomain, and a proline/serine/threonine (P/S/T)-rich C-terminal domain. The paired domain and paired-type homeodomain each have DNA binding activities, while the P/S/T-rich domain possesses a transactivation function. PAX6(5a) is a product of the alternatively spliced exon 5a resulting in a 14 residue insertion in the paired domain which alters the specificity of this DNA binding activity. The nucleotide sequence corresponding to the linker region encodes a set of three alternative translation start codons from which the third PAX6 isoform originates. Collectively known as the PAX6(ΔPD) or pairedless isoforms, these three gene products all lack a paired domain. The pairedless proteins possess molecular weights of 43, 33, or 32kDa, depending on the particular start codon used. PAX6 transactivation function is attributed to the variable length C-terminal P/S/T-rich domain which stretches to 153 residues in human and mouse proteins.
Experiments in mice demonstrate that a deficiency in Pax-6 leads to decrease in brain size, brain structure abnormality leading to Autism, lack of iris formation or a thin cornea. [ citation needed ] Knockout experiments produced eyeless phenotypes reinforcing indications of the gene's role in eye development. [7]
During embryological development the PAX6 gene, found on chromosome 2 in mice, can be seen expressed in multiple early structures such as the spinal cord, hindbrain, forebrain and eyes. [19] Mutations of the PAX6 gene in mammalian species can produce a drastic effect on the phenotype of the organism. This can be seen in mice that contain homozygous mutations of the 422 amino acid long transcription factor encoded by PAX6 in which they do not develop eyes or nasal cavities termed ‘small eye’ mice (PAX10sey/sey). [19] [20] Deletion of PAX6 induces the same abnormal phenotypes indicating that mutations cause the protein to lose functionality. PAX6 is essential is the formation of the retina, lens and cornea due to its role in early cell determination when forming precursors of these structures such as the optic vesicle and overlying surface ectoderm. [20] PAX10 mutations also hinder nasal cavity development due to the similar precursor structures that in small eye mice do not express PAX10 mRNA. [21] Mice lacking any functional pax6 begin to be phenotypically differentiable from normal mouse embryos at about day 9 to 10 of gestation. [22] The full elucidation of the precise mechanisms and molecular components by which the PAX6 gene influences eye, nasal and central nervous system development are still researched however, the study of PAX6 has brought more understanding to the development and genetic complexities of these mammalian body systems.
Aniridia is the absence of the iris, a muscular structure that opens and closes the pupil to allow light into the eye. It is also responsible for eye color. Without it, the central eye appears all black. It can be congenital, in which both eyes are usually involved, or caused by a penetrant injury. Isolated aniridia is a congenital disorder that is not limited to a defect in iris development, but is a panocular condition with macular and optic nerve hypoplasia, cataract, and corneal changes. Vision may be severely compromised and the disorder is frequently associated with some ocular complications: nystagmus, amblyopia, buphthalmos, and cataract. Aniridia in some individuals occurs as part of a syndrome, such as WAGR syndrome, or Gillespie syndrome.
Ectopic is a word used with a prefix, ecto, meaning “out of place.” Ectopic expression is an abnormal gene expression in a cell type, tissue type, or developmental stage in which the gene is not usually expressed. The term ectopic expression is predominantly used in studies using metazoans, especially in Drosophila melanogaster for research purposes.
In evolutionary developmental biology, Paired box (Pax) genes are a family of genes coding for tissue specific transcription factors containing an N-terminal paired domain and usually a partial, or in the case of four family members, a complete homeodomain to the C-terminus. An octapeptide as well as a Pro-Ser-Thr-rich C terminus may also be present. Pax proteins are important in early animal development for the specification of specific tissues, as well as during epimorphic limb regeneration in animals capable of such.
The PAX3 gene encodes a member of the paired box or PAX family of transcription factors. The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse Pax3 are present in a subfamily along with the highly homologous human PAX7 and mouse Pax7 genes. The human PAX3 gene is located in the 2q36.1 chromosomal region, and contains 10 exons within a 100 kb region.
The autoimmune regulator (AIRE) is a protein that in humans is encoded by the AIRE gene. It is a 13kb gene on chromosome 21q22.3 that has 545 amino acids. AIRE is a transcription factor expressed in the medulla of the thymus. It is part of the mechanism which eliminates self-reactive T cells that would cause autoimmune disease. It exposes T cells to normal, healthy proteins from all parts of the body, and T cells that react to those proteins are destroyed.
The steroidogenic factor 1 (SF-1) protein is a transcription factor involved in sex determination by controlling the activity of genes related to the reproductive glands or gonads and adrenal glands. This protein is encoded by the NR5A1 gene, a member of the nuclear receptor subfamily, located on the long arm of chromosome 9 at position 33.3. It was originally identified as a regulator of genes encoding cytochrome P450 steroid hydroxylases, however, further roles in endocrine function have since been discovered.
Wilms tumor protein (WT33) is a protein that in humans is encoded by the WT1 gene on chromosome 11p.
Paired box gene 2, also known as Pax-2, is a protein which in humans is encoded by the PAX2 gene.
SRY -box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 has a critical role in maintenance of embryonic and neural stem cells.
Paired box gene 8, also known as PAX8, is a protein which in humans is encoded by the PAX8 gene.
Paired box gene 4, also known as PAX4, is a protein which in humans is encoded by the PAX4 gene.
Paired box gene 9, also known as PAX9, is a protein which in humans is encoded by the PAX9 gene. It is also found in other mammals.
Transcription factor SOX-3 is a protein that in humans is encoded by the SOX3 gene. This gene encodes a member of the SOX family of transcription factors involved in the regulation of embryonic brain development and in determination of cell fate. The encoded protein acts as a transcriptional activator.
Homeobox protein OTX2 is a protein that in humans is encoded by the OTX2 gene.
Homeobox protein SIX3 is a protein that in humans is encoded by the SIX3 gene.
Veronica van Heyningen is an English geneticist who specialises in the etiology of anophthalmia as an honorary professor at University College London (UCL). She previously served as head of medical genetics at the MRC Human Genetics Unit in Edinburgh and the president of The Genetics Society. In 2014 she became president of the Galton Institute. As of 2019 she chairs the diversity committee of the Royal Society, previously chaired by Uta Frith.
Professor Nicholas Dixon Hastie CBE, FRS, FRSE is a British geneticist, and former Director of the MRC Human Genetics Unit at the University of Edinburgh.
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.
Pax-6, member of the Pax gene class, is responsible for carrying the genetic information that will encode Pax-6 (protein) which dictates the development of the olfactory epithelium, eyes and central nervous system in vertebrates. Pax-6 is expressed as a transcription factor when neural ectoderm receives a combination of weak sonic hedgehog and a strong TGF-Beta signaling gradients. Expression is first seen in the forebrain, hindbrain, head ectoderm and spinal cord followed by later expression in midbrain. Expression in the head ectoderm will give rise to the nasal placodes and to the eye placodes. The nasal placodes will give rise to the olfactory epithelium while eye placodes give rise to the lens and cornea. Expression in the different brain regions is orchestrated with the combinatorial expression of other transcription factors to give rise to the central nervous system. Experiments in mice demonstrate that a deficiency in Pax-6 leads to decrease in brain size, brain structure abnormality leading to Autism, lack of iris formation or a thin cornea. Knockout experiments produced eyeless phenotypes reinforcing the gene’s role in eye development. Advancing research in this area may lead us to better understanding of the complexity seen in neural development and maybe one day be able to grow eye tissue in vitro.
The evo-devo gene toolkit is the small subset of genes in an organism's genome whose products control the organism's embryonic development. Toolkit genes are central to the synthesis of molecular genetics, palaeontology, evolution and developmental biology in the science of evolutionary developmental biology (evo-devo). Many of them are ancient and highly conserved among animal phyla.
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