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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2009.08.003 Byline: Jason Clements (a)(b), Korneel Hens (a), Srinivas Merugu (b), Beatriz Dichtl (b), H. Gert de Couet (c), Patrick Callaerts (a)(b) Keywords: Eyeless; Pax6; Transcription factor; Paired domain; Homeodomain; Drosophila Abstract: Pax6 genes encode evolutionarily highly conserved transcription factors that are required for eye and brain development. Despite the characterization of mutations in Pax6 homologs in a range of organisms, and despite functional studies, it remains unclear what the relative importance is of the various parts of the Pax6 protein. To address this, we have studied the Drosophila Pax6 homolog eyeless. Specifically, we have generated new eyeless alleles, each with single missense mutations in one of the four domains of the protein. We show that these alleles result in abnormal eye and brain development while maintaining the OK107 eyeless GAL4 activity from which they were derived. We performed in vivo functional rescue experiments by expressing in an eyeless-specific pattern Eyeless proteins in which either the paired domain, the homeodomain, or the C-terminal domain was deleted. Rescue of the eye and brain phenotypes was only observed when full-length Eyeless was expressed, while all deletion constructs failed to rescue. These data, along with the phenotypes observed in the four newly characterized eyeless alleles, demonstrate the requirement for an intact Eyeless protein for normal Drosophila eye and brain development. They also suggest that some endogenous functions may be obscured in ectopic expression experiments. Author Affiliation: (a) Laboratory of Developmental Genetics, VIB, and Center of Human Genetics, Katholieke Universiteit Leuven, Herestraat 49, Box 602, B-3000, Leuven, Belgium (b) Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5001, USA (c) Department of Zoology, University of Hawaii at Manoa, Honolulu, HI 96822, USA Article History: Received 15 May 2009; Revised 28 July 2009; Accepted 3 August 2009