Midkine-a is required for cell cycle progression of Müller glia glia during neuronal regeneration in the vertebrate retina

In the retina of zebrafish, Muller glia have the ability to reprogram into stem cells capable of regenerating all classes of retinal neurons and restoring visual function. Understanding the cellular and molecular mechanisms controlling the stem cell properties of Muller glia in zebrafish may provide cues to unlock the regenerative potential in the mammalian nervous system. Midkine is a cytokine/growth factor with multiple roles in neural development, tissue repair and disease. In midkine-a loss-of-function mutants, of both sexes, Muller glia initiate the appropriate reprogramming response to photoreceptor death by increasing expression of stem cell-associated genesnd entering the G1 phase of the cell cycle. However, transition from G1 to S phase is blocked in the absence of Midkine-a, resulting in significantly reduced proliferation and selective failure to regenerate cone photoreceptors. . Failing to progress through the cell cycle, Muller glia undergo reactive gliosis pathological hallmark in the injured central nervous system of mammals. Finally, we determined that the Midkine-a receptor, Anaplastic Lymphoma Kinase, is upstream of the HLH regulatory protein, Id2and of the retinoblastoma gene, p130, which regulates progression through the cell cycle. These results demonstrate that Midkine-a functions as a core component of the mechanisms that regulate proliferation of stem cells in the injured central nervous system. SIGNIFICANCE STATEMENT The death of retinal neurons and photoreceptors is a leading cause of vision loss. Regenerating retinal neurons is a therapeutic goal. Zebrafish can regenerate retinal neurons from intrinsic stem cells, Muller gliand are a powerful model to understand how stem cells might be used therapeutically. Midkine-an injury-induced growth factor/cytokine that is expressed by Muller glia following neuronal death, is required for Muller glia to progress through the cell cycle. The absence of Midkine-a suspends proliferation and neuronal regeneration. With cell cycle progression stalled, Muller glia undergo reactive gliosis pathological hallmark of the mammalian retina. This work provides a unique insight into mechanisms that control the cell cycle during neuronal regeneration.