DNA Damage Response in Proliferating Müller Glia in the Mammalian Retina

Nomura-Komoike, Kaori; Saitoh, Fuminori; Komoike, Yuta; Fujieda, Hiroki

doi:10.1167/iovs.15-18101

Cited by 21 publications

(49 citation statements)

References 56 publications

(81 reference statements)

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“…There are also many studies indicating that Rac1 regulates cell cycle progression by upregulating cyclin D1, a key regulator of the G1/S transition 42,43 . As cyclin D1 expression is robustly increased in proliferating Müller glia after injury 5,44 , Rac1 may likely promote Müller glia proliferation by upregulating cyclin D1 expression. Accumulating evidence also indicates that Rac1 plays a key role in canonical Wnt signaling by promoting nuclear accumulation of β-catenin [45][46][47] .…”

Section: Discussionmentioning

confidence: 99%

“…Tissue preparation for immunohistochemistry was performed as described previously 5 . Briefly, the eyecups without lens were fixed with 4% paraformaldehyde in phosphate buffered saline (PBS) for 1 hour on ice, frozen in OCT compound (Leica Biosystems, Nussloch, Germany) with dry ice-isopentane, and cut on a cryostat into serial vertical sections of 10 μm through the optic disc along the dorsoventral axis.…”

Section: Methodsmentioning

confidence: 99%

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Phosphatidylserine recognition and Rac1 activation are required for Müller glia proliferation, gliosis and phagocytosis after retinal injury

Nomura-Komoike

Saitoh

Fujieda

2020

Sci Rep

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Müller glia, the principal glial cell type in the retina, have the potential to reenter the cell cycle after retinal injury. In mammals, proliferation of Müller glia is followed by gliosis, but not regeneration of neurons. Retinal injury is also accompanied by phagocytic removal of degenerated cells. We here investigated the possibility that proliferation and gliosis of Müller glia and phagocytosis of degenerated cells may be regulated by the same molecular pathways. After N-methyl-N-nitrosourea-induced retinal injury, degenerated photoreceptors were eliminated prior to the infiltration of microglia/macrophages into the outer nuclear layer, almost in parallel with cell cycle reentry of Müller glia. Inhibition of microglia/macrophage activation with minocycline did not affect the photoreceptor clearance. Accumulation of lysosomes and rhodopsin-positive photoreceptor debris within the cytoplasm of Müller glia indicated that Müller glia phagocytosed most photoreceptor debris. Pharmacological inhibition of phosphatidylserine and Rac1, key regulators of the phagocytic pathway, prevented cell cycle reentry, migration, upregulation of glial fibrillary acidic protein, and phagocytic activity of Müller glia. These data provide evidence that phosphatidylserine and Rac1 may contribute to the crosstalk between different signaling pathways activated in Müller glia after injury.Müller glia, the principal glial cells in the retina, possess a variety of functions to support retinal neurons and act to maintain retinal homeostasis under physiological as well as pathological conditions 1,2 . In lower vertebrates like fish, retinal injury induces Müller glia to proliferate and dedifferentiate to neuronal progenitor cells that are capable of regenerating retinal neurons 3,4 . In mammals, however, such regenerative capacity of Müller glia is extremely limited. In rats, for example, Müller glia proliferate in response to injury, but they quickly exit the cell cycle and many undergo cell death possibly by DNA damage response 5 . In addition, Müller glia in mammals show a set of injury-induced responses called reactive gliosis, including cellular hypertrophy, migration, and upregulation of intermediate filaments such as glial fibrillary acidic protein (GFAP) and vimentin 6 . Although gliosis may be neuroprotective, it may hamper tissue repair if the reaction is prolonged 6 .Previous evidence has indicated that the injury-induced responses of Müller glia are mediated by growth factors or cytokines secreted from damaged neurons, microglia, or Müller glia themselves 6-8 . A pioneering study by Rattner and Nathans 9 showed that damaged photoreceptors produce endothelin2 (Edn2), which signals onto Müller glia and induces their reactive responses such as GFAP upregulation. However, the Edn2-mediated interaction between damaged photoreceptors and Müller glia seems to be initiated by Leukemia inhibitory factor (LIF) release from Müller glia 10 . Upregulation of LIF has been observed in a variety of retinal injury models 10-13 , and TNFα may be i...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Phosphatidylserine recognition and Rac1 activation are required for Müller glia proliferation, gliosis and phagocytosis after retinal injury

Nomura-Komoike

Saitoh

Fujieda

2020

Sci Rep

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“…Müller cells entering S‐phase undergo DNA damage regardless of the type of retinal injury in mammals considering DDR associated with cell cycle reentry a unique feature of mammalian Müller cells (Nomura‐Komoike, Saitoh, Komoike, & Fujieda, ). Indeed, in zebrafish, retinal damage induces generation of Müller cell progenitors, which divide multiple times and form neurogenic cell clusters (Yurco & Cameron, ).…”

Section: Discussionmentioning

confidence: 99%

Retinal microglia signaling affects Müller cell behavior in the zebrafish following laser injury induction

Conedera

Pousa

Mercader

et al. 2019

Glia

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Microglia are the resident tissue macrophages of the central nervous system including the retina. Under pathophysiological conditions, microglia can signal to Müller cells, the major glial component of the retina, affecting their morphological, molecular, and functional responses. Microglia–Müller cell interactions appear to be bidirectional shaping the overall injury response in the retina. Hence, microglia and Müller cell responses to disease and injury have been ascribed both positive and negative outcomes. However, Müller cell reactivity and survival in the absence of immune cells after injury have not been investigated in detail in adult zebrafish. Here, we develop a model of focal retinal injury combined with pharmacological treatments for immune cell depletion in zebrafish. The retinal injury was induced by a diode laser to damage photoreceptors. Two pharmacological treatments were used to deplete either macrophage–microglia (PLX3397) or selectively eliminate peripheral macrophages (clodronate liposomes). We show that PLX3397 treatment hinders retinal regeneration in zebrafish, which is reversed by microglial repopulation. On the other hand, selective macrophage elimination did not affect the kinetics of retinal regeneration. The absence of retinal microglia and macrophages leads to dysregulated Müller cell behavior. In the untreated fish, Müller cells react after injury induction showing glial fibrillary acidic protein (GFAP), Phospho‐p44/42 MAPK (Erk1/2), and PCNA upregulation. However, in the immunosuppressed animals, GFAP and phospho‐p44/42 MAPK (Erk1/2) expression was not upregulated overtime and the reentry in the cell cycle was not affected. Thus, microglia and Müller cell signaling is pivotal to unlock the regenerative potential of Müller cells in order to repair the damaged retina.

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“…In adult retinas, Müller glia retain an intrinsic genetic program that is shared with these retinal progenitors (Roesch et al, 2008). Müller glia in mammalian retinas respond to neuronal death by entry into the cell cycle (Dyer and Cepko 2000;Hamon et al 2019;Rueda et al 2019;Joly et al, 2011;Nomura-Komoike et al, 2016). Importantly, in the mouse, genetic modifications that allow Müller glia to persistently express cyclin genes is sufficient to promote their mitotic division (Hamon et al, 2019;Rueda et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

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

Nagashima

D'Cruz

Hesse

et al. 2019

Preprint

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In zebrafish, Müller 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 Müller 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 Müller 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, Müller glia that fail to divide undergo reactive gliosis, a pathological hallmark of Müller glia in mammals. Finally, we show that activation of the Midkine-a receptor, ALK, is required for Müller glia proliferation. These data provide mechanistic insights into Müller glia stem cells in the vertebrate retina and suggest avenues for eliciting neuronal regeneration in mammals.

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DNA Damage Response in Proliferating Müller Glia in the Mammalian Retina

Abstract: Our findings suggest that the DNA damage response induced by unscheduled cell cycle reentry may be one of the mechanisms that limit the proliferative and regenerative capacity of Müller glia in the mammalian retina.

Cited by 21 publications

References 56 publications

Phosphatidylserine recognition and Rac1 activation are required for Müller glia proliferation, gliosis and phagocytosis after retinal injury

Phosphatidylserine recognition and Rac1 activation are required for Müller glia proliferation, gliosis and phagocytosis after retinal injury

Retinal microglia signaling affects Müller cell behavior in the zebrafish following laser injury induction

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

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