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

Nagashima, M., D'Cruz, T.S., Danku, A.E., Hesse, D., Sifuentes, C., Raymond, P.A., Hitchcock, P.F.
The Journal of neuroscience : the official journal of the Society for Neuroscience   40(6): 1232-1247 (Journal)
Registered Authors
Hitchcock, Peter, Nagashima, Mikiko, Raymond, Pamela
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Cell Cycle/physiology
  • Cell Dedifferentiation/physiology*
  • Cell Proliferation/physiology
  • Cellular Reprogramming/physiology*
  • Midkine/metabolism*
  • Nerve Regeneration/physiology*
  • Neural Stem Cells/cytology
  • Neural Stem Cells/metabolism
  • Neuroglia*/cytology
  • Neuroglia*/metabolism
  • Retina*/cytology
  • Retina*/metabolism
  • Zebrafish
  • Zebrafish Proteins/metabolism
31882403 Full text @ J. Neurosci.
In the retina of zebrafish, Müller 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 Müller 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, Müller 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, Müller 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 STATEMENTThe 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, Müller 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 Müller glia following neuronal death, is required for Müller glia to progress through the cell cycle. The absence of Midkine-a suspends proliferation and neuronal regeneration. With cell cycle progression stalled, Müller 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.
Genes / Markers
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Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes