Cellular expression ofMidkine-aandMidkine-bduring retinal development and photoreceptor regeneration in zebrafish

In the retina of adult teleosts, stem cells are sustained in two specialized niches: the ciliary marginal zone (CMZ) and the microenvironment surrounding adult Muller glia. Recently, Muller glia were identified as the regenerative stem cells in the teleost retina. Secreted signaling molecules that regu- late neuronal regeneration in the retina are largely unknown. In a microarray screen to discover such factors, we identi- fied midkine-b (mdkb). Midkine is a highly conserved heparin-binding growth factor with numerous biological functions. The zebrafish genome encodes two distinct mid- kine genes: mdka and mdkb. Here we describe the cellular expression of mdka and mdkb during retinal development and the initial, proliferative phase of photoreceptor regen- eration. The results show that in the embryonic and larval retina mdka and mdkb are expressed in stem cells, retinal progenitors, and neurons in distinct patterns that suggest different functions for the two molecules. Following the se- lective death of photoreceptors in the adult, mdka and mdkb are coexpressed in horizontal cells and proliferating Muller glia and their neurogenic progeny. These data reveal that Mdka and Mdkb are signaling factors present in the retinal stem cell niches in both embryonic and mature retinas, and that their cellular expression is actively modulated during retinal development and regeneration. J. Comp. Neurol. 514