Lens regeneration is a unique phenomenon restricted only to some urodeles. Upon lentectomy the new lens is formed by the transdifferentiation of the dorsal iris pigment epithelial cells (PECs). The ventral iris does not contribute to the process. What is interesting, however, is that when cells, from the ventral iris of the newt or from the pigmented epithelium (PE) of any animal including old humans, are placed in culture for long periods of time, they transdifferentiate to lens. In other words, PECs from many species are capable for lens regeneration, but in vivo, this capacity is unique to some newts only. The original hypothesis of this proposal was that there must be specific genes expressed in the dorsal versus the ventral iris of the newt eye that could help us identify factors that might regulate and induce lens regeneration. In previous years, we have studied expression patterns of several genes and we have identified several good candidates for such role. These genes were pax-6, six-3, FGFR-1 and prox-1. We then proposed that these genes could be used to transfect ventral PECs, which lack the ability to transdifferentiate to lens, in an attempt to induce lens regeneration. We have been successful with two different protocols. In one of them, ventral PECs were transfected with six-3 and treated with retinoic acid and in the other ventral irises were treated with a soluble inhibitor of the BMP pathway. These are the first cases of induction and we now would like to utilize this knowledge to understand the restriction of lens regeneration in other animals and to induce it. Having succeeded for the first time in inducing lens regeneration from the ventral iris, we now propose to examine the molecular pathways that are involved in the induction due to the treatments and to induce lens regeneration in other animals that are normally incompetent of lens regeneration, such as in the axolotl and mice. This might lead to experimentation with established animal models, which eventually can be used more efficiently in clinical applications.
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