PAX6
Pax in oculi
Ectopic expression of pax6 in Drosophila leads to the development of eyes in different organs: antenna (left) and legs (right). Image credit: Gehring WJ, Int J Dev Biol 2004
The eye is a complex structure, and its development is similarly complex. The PAX6 gene is a master transcription factor that regulates eye development across all species of animals, and is conserved from humans to fruit flies. PAX6 also plays major roles in the development of other organs, such as the brain and pancreas. PAX6 haploinsufficiency causes Aniridia, which is characterized by the absence of the iris in humans, and complete loss of PAX6 expression causes severe defects in the development of the eyes and brain. In order to regulate the development of these organs, the expression of PAX6 is orchestrated by more than 30 enhancer elements which form the PAX6 regulatory domain. This domain spans over 400 kilobases in the human genome, but is much smaller in other species. The vast differences in sizes of the PAX6 regulatory domains across different species, together with their high degree of conservation, make this an interesting locus for studying the relative positioning and spacing of regulatory elements. Specifically, we are interested in studying whether the distance between genes and regulatory elements is functionally relevant, or is a by-product of interspersed repetitive and non-functional DNA.
We are taking two major approaches to studying the PAX6 locus. One approach involves systematic removal of intergenic and repetitive DNA interspersing the genes and enhancer elements. Through a series of increasingly aggressive deletions of this intervening DNA, we expect to arrive at a much more compact yet still functional locus. The second approach involves replacing the entire locus in the human or mouse genome with one that is naturally more compact, namely that from the genome of the Japanese pufferfish Takifugu rubripes (Fugu), in which the PAX6 locus spans only around 80 kilobases compared the approximately 400 kilobases occupied by the human locus.
IN COLLABORATION WITH:
Wendy Bickmore, PhD, The University of Edinburgh