Pax6 is a selector gene responsible for modulating the fates of many distinct cell types, within several developing organs such as the eye, central nervous system and pancreas. The complex expression patterns and functions of Pax6 are achieved by tight re gulation, particularly at the level of transcription, of spatiotemporal and quantitative expression. A good illustration of the importance of Pax6 regulation are human eye anomalies caused by disruption of Pax6 transcriptional regulation as a result of de letions many kilobases (thousands of nucleotides) downstream of transcriptional termination at the polyA addition site. The Pax6 gene encodes a transcription factor that is highly conserved across species as evolutionarily distant as Homo sapiens, Drosoph ila melanogaster and Dugesia.tigrina. Pax6 has also been shown to be highly conserved, across mammals and more broadly across vertebrates, for genomic cis-regulatory sequences spanning 200 kb outside the transcribed gene. These two forms of conservation are good indicators that the functional genetic networks mediated by Pax6 are well conserved in evolution. The objectives of this project are to characterise the conserved elements extensively in different phyla (in insects, fishes, mammals and across ver tebrates). The aim is to reveal the dynamics of the Pax6 genetic network. To accomplish this we will combine the use of bioinformatics with lab experimentation on zebrafish and collaboratively in human, mouse and Drosophila. We will investigate the gene s that directly regulate Pax6 transcription and those which are immediate downstream targets of Pax6 using evolutionary information on cis-regulatory sequences of all the genes in the putative Pax6 network. Already known PAX6 interactors SOX2 and OTX2, al ready implicated in human eye disease, will also be studied. Iterative refinement of the bioinformatic predictions will be undertaken as wet-lab verification of initial results emerge.
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