Human Molecular Genetics Advance Access originally published online on January 27, 2005
Human Molecular Genetics 2005 14(6):735-745; doi:10.1093/hmg/ddi069
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Human Molecular Genetics, Vol. 14, No. 6 © Oxford University Press 2005; all rights reserved
The Pax6 isoform bearing an alternative spliced exon promotes the development of the neural retinal structure
1Department of Ophthalmology, National Center for Child Health and Development, Tokyo 157-8535, Japan, 2Department of Genetics, National Research Institute for Child Health and Development, Tokyo 154-8567, Japan, 3Department of Biological Information, Tokyo Institute of Technology, Graduate School of Bioscience and Biotechnology, Yokohama, 226-8501, Japan, 4Department of Laboratory Medicine, Kyorin University School of Medicine, Tokyo 181-8611, Japan, 5National Institute of Neuroscience, Tokyo 187-8502, Japan, 6Department of Developmental Neurobiology, Institute of Development, Aging and Cancer, Sendai 980-8575, Japan, 7Department of Neuroscience, University of Tokyo Graduate School of Medicine, Tokyo 113-0033, Japan, 8Division of Morphogenesis, Department of Embroyogenesis, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan and 9Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA
* To whom correspondence should be addressed at: Department of Ophthalmology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. Tel: +81 334160181; Fax: +81 334162222; Email: azuma-n{at}ncchd.go.jp
Received November 28, 2004; Accepted January 18, 2005
The vertebrate retina has an area where visual cells are closely packed for proper vision that is known as a fovea, an area centralis or a visual streak. The molecular mechanism that regulates the formation of these structures and visual cell gradients is unknown. The transcription factor Pax6 is a master regulator of eye development. A Pax6 isoform that contains an exon 5a-encoded 14 amino acid insertion in its paired domain, Pax6(+5a), has different DNA-binding properties compared with the Pax6(–5a) isoform. Little is known about the functional significance of Pax6(+5a). Here, we show that Pax6(+5a) is expressed especially in the retinal portion where visual cells accumulate during eye development and, when overexpressed, induces a remarkable well-differentiated retina-like structure. Pax6(+5a) proteins that bear point mutations that are found in patients with foveal hypoplasia are unable to induce these ectopic retina-like structures. We propose that Pax6(+5a) induces a developmental cascade in the prospective fovea, area centralis or visual streak region that leads to the formation of a retinal architecture bearing densely packed visual cells.
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