Midkine-a is required for cell cycle progression of Müller glia during neuronal regeneration

In zebrafish, Muller glia function as intrinsic retinal stem cells that can regenerate ablated neurons. Understanding the mechanisms governing neuronal stem cells may provide clues to regenerate neurons in mammals. We report that in Muller glia the cytokine/growth factor, Midkine-a, functions as a core autocrine regulator of the cell cycle. Utilizing midkine-a mutants, we determined that Midkine-a regulates elements of an Id2a-retinoblastoma network in reprogrammed Muller glia that controls the expression of cell cycle genes and is required for transition from G1 to S phases of the cell cycle. In mutants, Muller glia that fail to divide undergo reactive gliosis, a pathological hallmark of Muller glia in mammals. Finally, we show that activation of the Midkine-a receptor, ALK, is required for Muller glia proliferation. These data provide mechanistic insights into Muller glia stem cells in the vertebrate retina and suggest avenues for eliciting neuronal regeneration in mammals.