Collectively, these results suggest that upon retina removal at E

Collectively, these results suggest that upon retina removal at E4, the quiescent cells of the RPE dedifferentiate to become progenitor like cells similar to the cells of the optic vesicle that express the selleckchem AZD9291 combination of eye field transcriptional factors and the factors sox2, c myc and klf4. This process is transient and not sustained if no growth factors are present. FGF2 allows for the sustained transcriptional activity of sox2, c myc and klf4 in retinal pigmented epithelium undergoing reprogramming towards retina progenitors To analyze the effect on the levels of expression of the pluripotency inducing factors during the process of RPE transdifferentiation, we performed surgeries at E4 in which FGF2 heparin coated beads were placed in the optic cup as previously described.

Thereafter, the embryos were collected at different times. In contrast with the expression patterns during injury in the absence of FGF2, the alternative splice variants pax6 5a and 5a were up regulated sim ultaneously from 6 h to 72 h. RPE transdif ferentiation was confirmed by a significant decrease in expression of mitf and tyr at 72 h PR. Immu nostaining revealed that c Myc, Sox2, Klf4 and the retina progenitor markers Pax6 and Chx10 were present at 72 h PR in the transdifferentiated RPE. In the absence of FGF2 at 72 h PR, the RPE did not trans differentiate and remained pigmented, expressing only c Myc, Klf4 and Lin 28, just as it does during normal development. As ex pected, in addition to transdifferentiated RPE, we also observed retina regeneration from the pool of stem progenitor cells located in the ciliary margin of the chick eye.

Thus, we conclude that FGF2 allows the sustained expression of sox2 and c myc in retina progenitor cells along with eye field transcrip tional factors to complete the transdifferentiation pro gram of the RPE. In agreement with our results, destruction of photore ceptors by acute light lesions in zebrafish central retina re sults in M��ller glia dedifferentiation 4 to 8 h post lesion, exemplified by a strong Rx1 immunoreactivity. We found a significant up regulation of rx1 transcript at 6 h post injury during the transient dedifferentiation of the RPE. Moreover, at 24 h post lesion, a per centage of the activated zebrafish M��ller glia cells re enter the cell cycle, just as the chick RPE does in the presence of FGF2.

Interestingly, M��ller glia cells respond by dedifferenti ating after local loss of contact with photoreceptors, however, this dedifferentiation is not enough to promote re entry to the cell cycle. Similarly, it is possible that the loss of contact between the RPE and the retina triggers the process of RPE dediffer entiation, or that the research use process involves an inflammation molecule such as TNF, as in zebrafish, or even ana phylatoxins such as C3a or interleukins like IL 6, which have been shown to play a role in chick retina regeneration.

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