Transdifferentiation of the retinal pigment epithelia to the neural retina by transfer of the Pax6 transcriptional factor.
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.
Azuma
Noriyuki
N
Department of Ophthalmology, National Center for Child Health and Development, Tokyo 157-8535, Japan. azuma-n@ncchd.go.jp
Tadokoro
Keiko
K
Asaka
Astuko
A
Yamada
Masao
M
Yamaguchi
Yuki
Y
Handa
Hiroshi
H
Matsushima
Satsuki
S
Watanabe
Takashi
T
Kida
Yasuyuki
Y
Ogura
Toshihiko
T
Torii
Masaaki
M
Shimamura
Kenji
K
Nakafuku
Masato
M
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics* / Q000502:physiology; D002642:Chick Embryo; D018274:Electroporation; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D018014:Gene Transfer Techniques; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000166:cytology*
D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D005346:Fibroblast Growth Factors