PAX6

Paired box protein Pax-6 also known as aniridia type II protein (AN2) or oculorhombin is a is_associated_with::protein that in humans is encoded by the PAX6 is_associated_with::gene. Pax6 is a transcription factor present during embryonic development. The encoded protein contains two different binding sites that are known to bind DNA and function as regulators of gene transcription. It is a key regulatory gene of eye and brain development. Within the brain, the protein is involved in development of the specialized cells that process smell. As a transcription factor, Pax6 activates and/or deactivates gene expression patterns to ensure for proper development of the tissue. Mutations of the Pax6 gene are known to cause various disorders of the eyes. Two common disorders associated with a mutation are: aniridia, the absence of the iris, and Peter’s anomaly, thinning and clouding of the cornea. Scientists have created a “knockout” model using mice during which time the mouse does not express Pax6. The ‘knockout” model is eyeless or has very underdeveloped eyes further indicating Pax6 is required for proper eye development.

Function
PAX6 is a member of the is_associated_with::Pax gene family. 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 is_associated_with::ectodermal tissues. 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. This is_associated_with::transcription factor is most noted for its use in the interspecifically induced expression of ectopic eyes and is of medical importance because is_associated_with::heterozygous mutants produce a wide spectrum of ocular defects such as is_associated_with::Aniridia in humans.

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 is_associated_with::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 is_associated_with::DNA binding domain of Pax6 utilizes two DNA-binding domains, the paired domain (PD), and the paired-type is_associated_with::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.

Species distribution


PAX6 protein function is highly conserved across is_associated_with::bilaterian species. For instance, mouse PAX6 can trigger eye development in is_associated_with::Drosophila melanogaster. Additionally, mouse and human PAX6 have identical amino acid sequences.

Genomic organisation of the PAX6 locus varies considerably among species, including the number and distribution of is_associated_with::exons, is_associated_with::cis-regulatory elements, and is_associated_with::transcription start sites. 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 2 confirmed promoters (P0 and P1), 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.

Of the four is_associated_with::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.

Isoforms
The vertebrate PAX6 locus encodes at least three different protein is_associated_with::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.