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Midkine-a Is Required for Cell Cycle Progression of Müller Glia during Neuronal Regeneration in the Vertebrate Retina.
J Neurosci. 2020 02 05; 40(6):1232-1247.JN

Abstract

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 genes, and 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, a pathological hallmark in the injured CNS of mammals. Finally, we determined that the Midkine-a receptor, anaplastic lymphoma kinase, is upstream of the HLH regulatory protein, Id2a, and 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 CNS.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, Müller glia, and are a powerful model to understand how stem cells might be used therapeutically. Midkine-a, 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, a pathological hallmark of the mammalian retina. This work provides a unique insight into mechanisms that control the cell cycle during neuronal regeneration.

Authors+Show Affiliations

Department of Ophthalmology and Visual Sciences, and.Department of Ophthalmology and Visual Sciences, and.Department of Ophthalmology and Visual Sciences, and.Department of Ophthalmology and Visual Sciences, and.Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48105.Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48105.Department of Ophthalmology and Visual Sciences, and peterh@umich.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31882403

Citation

Nagashima, Mikiko, et al. "Midkine-a Is Required for Cell Cycle Progression of Müller Glia During Neuronal Regeneration in the Vertebrate Retina." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 40, no. 6, 2020, pp. 1232-1247.
Nagashima M, D'Cruz TS, Danku AE, et al. Midkine-a Is Required for Cell Cycle Progression of Müller Glia during Neuronal Regeneration in the Vertebrate Retina. J Neurosci. 2020;40(6):1232-1247.
Nagashima, M., D'Cruz, T. S., Danku, A. E., Hesse, D., Sifuentes, C., Raymond, P. A., & Hitchcock, P. F. (2020). Midkine-a Is Required for Cell Cycle Progression of Müller Glia during Neuronal Regeneration in the Vertebrate Retina. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 40(6), 1232-1247. https://doi.org/10.1523/JNEUROSCI.1675-19.2019
Nagashima M, et al. Midkine-a Is Required for Cell Cycle Progression of Müller Glia During Neuronal Regeneration in the Vertebrate Retina. J Neurosci. 2020 02 5;40(6):1232-1247. PubMed PMID: 31882403.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Midkine-a Is Required for Cell Cycle Progression of Müller Glia during Neuronal Regeneration in the Vertebrate Retina. AU - Nagashima,Mikiko, AU - D'Cruz,Travis S, AU - Danku,Antoinette E, AU - Hesse,Doneen, AU - Sifuentes,Christopher, AU - Raymond,Pamela A, AU - Hitchcock,Peter F, Y1 - 2019/12/27/ PY - 2019/07/15/received PY - 2019/11/27/revised PY - 2019/12/17/accepted PY - 2019/12/29/pubmed PY - 2020/8/18/medline PY - 2019/12/29/entrez KW - neurogenesis KW - photoreceptors KW - proliferation KW - reprogramming KW - zebrafish SP - 1232 EP - 1247 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 40 IS - 6 N2 - 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 genes, and 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, a pathological hallmark in the injured CNS of mammals. Finally, we determined that the Midkine-a receptor, anaplastic lymphoma kinase, is upstream of the HLH regulatory protein, Id2a, and 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 CNS.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, Müller glia, and are a powerful model to understand how stem cells might be used therapeutically. Midkine-a, 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, a pathological hallmark of the mammalian retina. This work provides a unique insight into mechanisms that control the cell cycle during neuronal regeneration. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/31882403/Midkine_a_Is_Required_for_Cell_Cycle_Progression_of_Müller_Glia_during_Neuronal_Regeneration_in_the_Vertebrate_Retina_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=31882403 DB - PRIME DP - Unbound Medicine ER -