Mitotic activation of proliferative cells in the inner nuclear layer of the mature fish retina: Regulatory signals and molecular markers

New neurons continuously differentiate within the otherwise mature retina of teleost fish, both under normal conditions and in response to injury. We investigated the effects of surgical injury and intraocular injection of neurotrophic factors on the mitotic rate of proliferative inner nuclear layer cells (PINC). PINC are continually born in the inner nuclear layer and then migrate to the outer nuclear layer (ONL). Surgical excision of a part of a retina activates PINC mitotic activity near and far from the lesion. In the injured eye, up-regulation of PINC cells is largest in the dorsonasal sector of the retina, regardless of the site of lesion. Up-regulation extends even to the unlesioned contralateral eye, where it occurs in the same dorsonasal sector. Intraocular injection of ciliary neurotrophic factor mimics the effect of injury on PINC in the treated eye but not on the untreated contralateral retina. We searched for the expression in PINC of Pax6, a transcription factor linked to retinal progenitor cells and found that less than 0.5% of all PINC cells express it. Importantly, the number of Pax6-expressing PINC does not change significantly in the retinas subjected to any of the experimental manipulations tested. Under normal conditions, the default fate of PINC cells is to migrate to the ONL and, likely, replenish the rod progenitor pool. PINC respond to injury (both surgical and light-dependent) by increasing their mitotic rate; this increase is long lived, but there are no changes in the expression level of Pax6. PINC probably are a heterogenous cell population that can be specified for ultimate, different purposes: creating rod precursors, creating founder cells, creating cone precursors. Several fates are recognized now, but others may also be possible.