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Jena Chojnowski, Jorn Lakowski, Kenji Johnson, James D Lauderdale; Fishing for evolutionarily conserved Pax6 eye enhancers in mice. Invest. Ophthalmol. Vis. Sci. 2014;55(13):700.
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© ARVO (1962-2015); The Authors (2016-present)
To identify evolutionarily conserved cis-regulatory elements that mediate different aspects of PAX6 expression in the developing vertebrate eye. The PAX6 transcription factor plays several roles in eye development, including control of cell proliferation, maintenance of the retinogenic potential of progenitor cells, and cell fate specification. These roles in turn are mediated by modular cis-regulatory elements that are widely spaced within the Pax6 locus. Although a number of elements have been identified, the regulatory mechanisms governing several aspects of PAX6 expression remain poorly understood.
We have taken a comparative approach using mouse and zebrafish to investigate Pax6 transcriptional regulation. Whereas mouse has a single Pax6 transcript unit, zebrafish have two Pax6 genes (Pax6a and Pax6b) and Pax6 regulatory elements have been partitioned between them. Mice harboring either Pax6a or Pax6b bacterial artificial chromosome (BAC) reporter transgenes were generated. Reporter gene expression was assessed in eyes of developing mouse embryos and compared to endogenous PAX6 expression.
The Pax6a and Pax6b BAC reporter transgenes exhibit overlapping and distinct patterns of expression in the developing mouse eye. Pax6a expression more closely replicates that of the mouse gene, and is expressed in the surface ectoderm, lens, retina, and retinal pigmented epithelium of the developing optic cup. As development progresses, Pax6a transgene expression is detected in retinal ganglion cells, amacrine cells, horizontal cells, and Müller glia of the mature retina and also in anterior structures of the eye. Interestingly, the Pax6b transgene exhibits a more restricted spatiotemporal expression pattern in the developing eye suggesting the action of distinct cis-regulatory modules.
Many if not most of the cis-acting regulatory sequences governing Pax6 transcription in both mice and zebrafish have been functionally conserved throughout evolution. This functional conservation in combination with comparative genomic data provides a robust framework for the identification of novel PAX6 regulatory elements and a deeper understanding of Pax6 regulatory mechanisms.
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