Human Molecular Genetics Advance Access originally published online on March 9, 2005
Human Molecular Genetics 2005 14(8):1059-1068; doi:10.1093/hmg/ddi098
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Transdifferentiation of the retinal pigment epithelia to the neural retina by transfer of the Pax6 transcriptional factor
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 Clinical Research Medicine, Kyorin University School of Medicine, Tokyo 181-8611, Japan, 5Department of Developmental Neurobiology, Institute of Development, Aging and Cancer, Sendai 980-8575, Japan, 6Department of Neuroscience, University of Tokyo Graduate School of Medicine, Tokyo 113-0033, Japan, 7Division of Morphogenesis, Department of Embryogenesis, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan and 8Division 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, Seatagaya-ku, Tokyo 157-8535, Japan. Tel: +81 334160181; Fax: 81 334162222; Email: azuma-n{at}ncchd.go.jp
Received December 19, 2004; Accepted March 2, 2005
The Pax6 gene plays an important role in eye morphogenesis throughout the animal kingdom. The Pax6 gene and its homologue could form ectopic eyes by targeted expression in Drosophila and Xenopus. Thus, this gene is a master gene for the eye morphogenesis at least in these animals. In the early development of the vertebrate eye, Pax6 is required for the instruction of multipotential progenitor cells of the neural retina (NR). Primitive retinal pigment epithelial (RPE) cells are able to switch their phenotype and differentiate into NR under exogenous intervention, including treatment with fibroblast growth factors (FGFs), and surgical removal of endogenous NR. However, the molecular basis of phenotypic switching is still controversial. Here, we show that Pax6 alone is sufficient to induce transdifferentiation of ectopic NR from RPE cells without addition of FGFs or surgical manipulation. Pax6-mediated transdifferentiation can be induced even at later stages of development. Both in vivo and in vitro studies show that the Pax6 lies downstream of FGF signaling, highlighting the central roles of Pax6 in NR transdifferentiation. Our results provide an evidence of retinogenic potential of nearly mature RPE and a cue for new therapeutic approaches to regenerate functional NR in patients with a visual loss.
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