Pax genes

Paired box (Pax) genes are a family of tissue specific transcription factors containing a PAIRED domain and usually a partial or complete homeodomain. An octapeptide 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.

Within the mammalian family, there are four well defined groups of Pax genes.

• Pax group 1 (Pax 1 and 9),
• Pax group 2 (Pax 2, 5 and 8),
• Pax group 3 (Pax 3 and 7) and
• Pax group 4 (Pax 4 and 6).

Orthologous genes exist throughout the Metazoa, including extensive study of the ectopic expression in Drosophila using murine Pax6.

PAX1

PAX1 has been identified in mice with the development of vertebrate and embryo segmentation, and some evidence this is also true in humans. It transcribes a 440 amino acid protein from 4 exons and 1,323bps in humans.

PAX2

PAX2 has been identified with kidney and optic nerve development. It transcribes a 417 amino acid protein from 11 exons and 4,261 bps in humans. Mutation of PAX2 in humans has been associated with renal-coloboma syndrome as well as oligomeganephronia.

PAX3

PAX3 has been identified with ear, eye and facial development. It transcribes a 479 amino acid protein in humans. Mutations in it can cause Waardenburg syndrome. It is expressed in early embryonic phases in dermatomyotome of paraxial mesoderm which it helps to demarcate. In that way PAX3 contributes to early striated muscle development since all myoblasts are derived from dermatomyotome of paraxial mesoderm. Interestingly, PAX3/FKHR fusion gene is often found in some forms of rhabdomyosarcoma, a kind of cancer arisen from striated muscle cells.

PAX4

PAX4 has been identified with pancreatic islet beta cells. It transcribes a 350 amino acid protein from 9 exons and 2,010 bps in humans.

PAX5

PAX5 has been identified with neural and spermatogenesis development. It transcribes a 391 amino acid protein from 10 exons and 3,644bps in humans.

PAX6

PAX6 is the most researched and appears throughout the literature as a "master control" gene for the development of eyes and sensory organs, certain neural and epidermal tissues as well as other homologous structures, usually derived from ectodermal tissues. This transcription factor is most famous 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.

PAX6 protein is highly conserved across species, and for instance mouse PAX6 can trigger eye development in Drosophila melanogaster.

Genomic organisation of the PAX6 locus varies considerably between species, including the number and distribution of exons, cis-regulatory elements, and transcription start sites. The first work on genomic organisation was performed in quail, although 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.

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 prolein/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.

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.

PAX7

PAX7 has been possibly associated with myogenesis. It transcribes a protein of 520 amino acids from 8 exons and 2,260bps in humans. PAX7 is required for the developmental specification of satellite cells in skeletal muscle.

PAX8

PAX8 has been associated with thyroid specific expression. It transcribes a protein of 451 amino acids from 11 exons and 2,526bps in humans.

PAX9

PAX9 has found to be associated with a number of organ and other skeletal developments, particularly teeth. It transcribes a protein of 341 amino acids from 4 exons and 1,644bps in humans.

See also

• Homeobox
• Evolutionary developmental biology
• Body plan
• SOX genes

References

• Zuker, Charles S. (1994). "On the evolution of eyes: would you like it simple or compound?". Science. 265 (5173). PMID 8047881. {{cite journal}}: Cite has empty unknown parameter: |1= (help); Unknown parameter |month= ignored (help)
• Quiring, Rebecca (1994). "Homology of the eyeless gene of Drosophila to the small eye gene in mice and Aniridia in humans". Science. 265 (5173). PMID 7914031. {{cite journal}}: Cite has empty unknown parameter: |1= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)

External links

• A Review of the Highly Conserved PAX6 Gene in Eye Development Regulation
• Pax+Transcription+Factors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)