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Actin-Cytoskeleton- and Rock-Mediated INM Are Required for Photoreceptor Regeneration in the Adult Zebrafish Retina.
J Neurosci. 2015 Nov 25; 35(47):15612-34.JN

Abstract

Loss of retinal neurons in adult zebrafish (Danio rerio) induces a robust regenerative response mediated by the reentry of the resident Müller glia into the cell cycle. Upon initiating Müller glia proliferation, their nuclei migrate along the apicobasal axis of the retina in phase with the cell cycle in a process termed interkinetic nuclear migration (INM). We examined the mechanisms governing this cellular process and explored its function in regenerating the adult zebrafish retina. Live-cell imaging revealed that the majority of Müller glia nuclei migrated to the outer nuclear layer (ONL) to divide. These Müller glia formed prominent actin filaments at the rear of nuclei that had migrated to the ONL. Inhibiting actin filament formation or Rho-associated coiled-coil kinase (Rock) activity, which is necessary for phosphorylation of myosin light chain and actin myosin-mediated contraction, disrupted INM with increased numbers of mitotic nuclei remaining in the basal inner nuclear layer, the region where Müller glia typically reside. Double knockdown of Rho-associated coiled-coil kinase 2a (Rock2a) and Rho-associated coiled-coil kinase 2b (Rock2b) similarly disrupted INM and reduced Müller glial cell cycle reentry. In contrast, Rock inhibition immediately before the onset of INM did not affect Müller glia proliferation, but subsequently reduced neuronal progenitor cell proliferation due to early cell cycle exit. Long-term, Rock inhibition increased the generation of mislocalized ganglion/amacrine cells at the expense of rod and cone photoreceptors. In summary, INM is driven by an actin-myosin-mediated process controlled by Rock2a and Rock2b activity, which is required for sufficient proliferation and regeneration of photoreceptors after light damage.

SIGNIFICANCE STATEMENT

The human retina does not replace lost or damaged neurons, ultimately causing vision impairment. In contrast, zebrafish are capable of regenerating lost neurons. Understanding the mechanisms that regulate retinal regeneration in these organisms will help to elucidate approaches to stimulate a similar response in humans. In the damaged zebrafish retina, Müller glia dedifferentiate and proliferate to generate neuronal progenitor cells (NPCs) that differentiate into the lost neurons. We show that the nuclei of Müller glia and NPCs migrate apically and basally in phase with the cell cycle. This migration is facilitated by the actin cytoskeleton and Rho-associated coiled-coil kinases (Rocks). We demonstrate that Rock function is required for sufficient proliferation and the regeneration of photoreceptors, likely via regulating nuclear migration.

Authors+Show Affiliations

Department of Biological Sciences and the Center for Zebrafish Research, Galvin Life Sciences Building, University of Notre Dame, Notre Dame, Indiana 46556.Department of Biological Sciences and the Center for Zebrafish Research, Galvin Life Sciences Building, University of Notre Dame, Notre Dame, Indiana 46556.Department of Biological Sciences and the Center for Zebrafish Research, Galvin Life Sciences Building, University of Notre Dame, Notre Dame, Indiana 46556.Department of Biological Sciences and the Center for Zebrafish Research, Galvin Life Sciences Building, University of Notre Dame, Notre Dame, Indiana 46556 dhyde@nd.edu.

Pub Type(s)

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

Language

eng

PubMed ID

26609156

Citation

Lahne, Manuela, et al. "Actin-Cytoskeleton- and Rock-Mediated INM Are Required for Photoreceptor Regeneration in the Adult Zebrafish Retina." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 35, no. 47, 2015, pp. 15612-34.
Lahne M, Li J, Marton RM, et al. Actin-Cytoskeleton- and Rock-Mediated INM Are Required for Photoreceptor Regeneration in the Adult Zebrafish Retina. J Neurosci. 2015;35(47):15612-34.
Lahne, M., Li, J., Marton, R. M., & Hyde, D. R. (2015). Actin-Cytoskeleton- and Rock-Mediated INM Are Required for Photoreceptor Regeneration in the Adult Zebrafish Retina. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 35(47), 15612-34. https://doi.org/10.1523/JNEUROSCI.5005-14.2015
Lahne M, et al. Actin-Cytoskeleton- and Rock-Mediated INM Are Required for Photoreceptor Regeneration in the Adult Zebrafish Retina. J Neurosci. 2015 Nov 25;35(47):15612-34. PubMed PMID: 26609156.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Actin-Cytoskeleton- and Rock-Mediated INM Are Required for Photoreceptor Regeneration in the Adult Zebrafish Retina. AU - Lahne,Manuela, AU - Li,Jingling, AU - Marton,Rebecca M, AU - Hyde,David R, PY - 2015/11/27/entrez PY - 2015/11/27/pubmed PY - 2016/3/15/medline KW - Müller glia KW - Rho-associated coiled-coil kinases KW - actin cytoskeleton KW - interkinetic nuclear migration KW - retinal regeneration SP - 15612 EP - 34 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 35 IS - 47 N2 - UNLABELLED: Loss of retinal neurons in adult zebrafish (Danio rerio) induces a robust regenerative response mediated by the reentry of the resident Müller glia into the cell cycle. Upon initiating Müller glia proliferation, their nuclei migrate along the apicobasal axis of the retina in phase with the cell cycle in a process termed interkinetic nuclear migration (INM). We examined the mechanisms governing this cellular process and explored its function in regenerating the adult zebrafish retina. Live-cell imaging revealed that the majority of Müller glia nuclei migrated to the outer nuclear layer (ONL) to divide. These Müller glia formed prominent actin filaments at the rear of nuclei that had migrated to the ONL. Inhibiting actin filament formation or Rho-associated coiled-coil kinase (Rock) activity, which is necessary for phosphorylation of myosin light chain and actin myosin-mediated contraction, disrupted INM with increased numbers of mitotic nuclei remaining in the basal inner nuclear layer, the region where Müller glia typically reside. Double knockdown of Rho-associated coiled-coil kinase 2a (Rock2a) and Rho-associated coiled-coil kinase 2b (Rock2b) similarly disrupted INM and reduced Müller glial cell cycle reentry. In contrast, Rock inhibition immediately before the onset of INM did not affect Müller glia proliferation, but subsequently reduced neuronal progenitor cell proliferation due to early cell cycle exit. Long-term, Rock inhibition increased the generation of mislocalized ganglion/amacrine cells at the expense of rod and cone photoreceptors. In summary, INM is driven by an actin-myosin-mediated process controlled by Rock2a and Rock2b activity, which is required for sufficient proliferation and regeneration of photoreceptors after light damage. SIGNIFICANCE STATEMENT: The human retina does not replace lost or damaged neurons, ultimately causing vision impairment. In contrast, zebrafish are capable of regenerating lost neurons. Understanding the mechanisms that regulate retinal regeneration in these organisms will help to elucidate approaches to stimulate a similar response in humans. In the damaged zebrafish retina, Müller glia dedifferentiate and proliferate to generate neuronal progenitor cells (NPCs) that differentiate into the lost neurons. We show that the nuclei of Müller glia and NPCs migrate apically and basally in phase with the cell cycle. This migration is facilitated by the actin cytoskeleton and Rho-associated coiled-coil kinases (Rocks). We demonstrate that Rock function is required for sufficient proliferation and the regeneration of photoreceptors, likely via regulating nuclear migration. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/26609156/Actin_Cytoskeleton__and_Rock_Mediated_INM_Are_Required_for_Photoreceptor_Regeneration_in_the_Adult_Zebrafish_Retina_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=26609156 DB - PRIME DP - Unbound Medicine ER -