Upregulation of Leukemia Inhibitory Factor (LIF) during the Early Stage of Optic Nerve Regeneration in Zebrafish

Ogai, Kazuhiro; Kuwana, Ayaka; Hisano, Suguru; Nagashima, Mikiko; Koriyama, Yoshiki; Sugitani, Kayo; Mawatari, Kazuhiro; Nakashima, Hiroshi; Kato, Satoru

doi:10.1371/journal.pone.0106010

Cited by 29 publications

(26 citation statements)

References 59 publications

(86 reference statements)

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“…Thus, it was unexpected to see only LIF, and not also IL-6, mRNA increase with CCL2 overexpression. We also assayed the expression of two known gp130 cytokine/STAT3-dependent genes, galanin and GAP-43 (Ogai et al, 2014; Qiu et al, 2005; Rao et al, 1993; Zigmond, 2012) and found that their expression remained unchanged following CCL2 overexpression. Although initially surprising, this may indicate that LIF-induced gene expression requires more than a 4-fold increase in the cytokine.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the monocyte chemokine CCL2 in dorsal root ganglion neurons causes a conditioning-like increase in neurite outgrowth and does so via a STAT3 dependent mechanism

Niemi

DeFrancesco-Lisowitz

Cregg

et al. 2016

Experimental Neurology

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Neuroinflammation plays a critical role in the regeneration of peripheral nerves following axotomy. An injury to the sciatic nerve leads to significant macrophage accumulation in the L5 DRG, an effect not seen when the dorsal root is injured. We recently demonstrated that this accumulation around axotomized cell bodies is necessary for a peripheral conditioning lesion response to occur. Here we asked whether overexpression of the monocyte chemokine CCL2 specifically in DRG neurons of uninjured mice is sufficient to cause macrophage accumulation and to enhance regeneration or whether other injury-derived signals are required. AAV5-EF1α-CCL2 was injected intrathecally, and this injection led to a time-dependent increase in CCL2 mRNA expression and macrophage accumulation in L5 DRG, with a maximal response at 3 wk post-injection. These changes led to a conditioning-like increase in neurite outgrowth in DRG explant and dissociated cell cultures. This increase in regeneration was dependent upon CCL2 acting through its primary receptor CCR2. When CCL2 was overexpressed in CCR2 −/− mice, macrophage accumulation and enhanced regeneration were not observed. To address the mechanism by which CCL2 overexpression enhances regeneration, we tested for elevated expression of regeneration-associated genes in these animals. Surprisingly, we found that CCL2 overexpression led to a selective increase in LIF mRNA and neuronal phosphorylated STAT3 (pSTAT3) in L5 DRGs, with no change in expression seen in other RAGs such as GAP-43. Blockade of STAT3 phosphorylation by each of two different inhibitors prevented the increase in neurite outgrowth. Thus, CCL2 overexpression is sufficient to induce macrophage accumulation in uninjured L5 DRGs and increase the regenerative capacity of DRG neurons via a STAT3-dependent mechanism.

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Section: Discussionmentioning

confidence: 99%

Overexpression of the monocyte chemokine CCL2 in dorsal root ganglion neurons causes a conditioning-like increase in neurite outgrowth and does so via a STAT3 dependent mechanism

Niemi

DeFrancesco-Lisowitz

Cregg

et al. 2016

Experimental Neurology

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“…Likewise, porcine retinal explants are mostly used to analyze neuroprotection and cell survival, rather than neurite outgrowth MartinezFernandez;de la Camara et al 2014;Taylor et al 2014;Bell et al 2016). Regarding anamniote models, retinal explants harvested from goldfish or zebrafish have also been used to test the putative effect of both intrinsic and extrinsic factors on RGC outgrowth/regeneration, albeit to a more limited extend (Nusetti et al 2005;Veldman et al 2007Veldman et al , 2010Cubillan et al 2012;Ou et al 2012;Ogai et al 2014). To culture fish retinal explants, retinas are chopped into small squares and transferred to poly-L-lysine-coated well plates.…”

Section: Ex Vivo Tissue Explant Studies In Other Vertebratesmentioning

confidence: 99%

“…To culture fish retinal explants, retinas are chopped into small squares and transferred to poly-L-lysine-coated well plates. After an incubation period of 1-4 days, the number of neurites, their length and/or density can be quantified (Becker and Becker 2002;Becker et al 2004;Veldman et al 2007Veldman et al , 2010Elsaeidi et al 2014;Ogai et al 2014;Welte et al 2015;Van Houcke et al 2017). …”

Section: Ex Vivo Tissue Explant Studies In Other Vertebratesmentioning

confidence: 99%

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Complementary research models and methods to study axonal regeneration in the vertebrate retinofugal system

et al. 2017

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Due to the lack of axonal regeneration, age-related deterioration in the central nervous system (CNS) poses a significant burden on the wellbeing of a growing number of elderly. To overcome this regenerative failure and to improve the patient's life quality, the search for novel regenerative treatment strategies requires valuable (animal) models and techniques. As an extension of the CNS, the retinofugal system, consisting of retinal ganglion cells that send their axons along the optic nerve to the visual brain areas, has importantly contributed to the current knowledge on mechanisms underlying the restricted regenerative capacities and to the development of novel strategies to enhance axonal regeneration. It provides an extensively used research tool, not only in amniote vertebrates including rodents, but also in anamniote vertebrates, such as zebrafish. Indeed, the latter show robust regeneration capacities, thereby providing insights into the factors that contribute to axonal regrowth and proper guidance, complementing studies in mammals. This review provides an integrative and critical overview of the classical and state-of-the-art models and methods that have been employed in the retinofugal system to advance our knowledge on the signaling pathways underlying the restricted versus robust axonal regeneration in rodents and zebrafish, respectively. In vitro, ex vivo and in vivo models and techniques to improve the visualization and analysis of regenerating axons are summarized. As such, the retinofugal system is presented as a valuable model to further facilitate research on axonal regeneration and to open novel therapeutic avenues for CNS pathologies.

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“…Generally, fish central nervous system (CNS) neurons can regenerate even after nerve transection, whereas mammalian CNS neurons cannot [17][18][19]. We have previously cloned RAGs from the axotomized zebrafish visual system, including the retina, and found that they are largely classified into two groups: one that displays anti-oxidant or anti-apoptotic activity and another that displays neurite outgrowth activity [19][20][21][22][23][24][25][26]. The former type can be induced at an early stage of nerve regeneration immediately after optic nerve injury, whereas the latter can typically be induced at a later stage of nerve regeneration [19].…”

Section: Introductionmentioning

confidence: 99%

A novel function of neuroglobin for neuroregeneration in mice after optic nerve injury

Sugitani

Koriyama

Sera

et al. 2017

Biochemical and Biophysical Research Communications

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Neuroglobin (Ngb) is a recently discovered heme protein in the vertebrate brain that can bind to oxygen molecules. Mammalian Ngb plays a crucial role in neuroprotection under conditions of oxidative stress. To investigate other potential functions of Ngb, we investigated the mouse retinal Ngb system following optic nerve injury. In the retina of control mice, Ngb immunoreactivity was limited to the retinal ganglion cell (RGC) layer, and this immunoreactivity rapidly decreased to less than 50% of the control level 5 days after optic nerve injury. On the basis of this decrease, we designed in vivo experiments with enhanced expression of Ngb using adult mouse retina. The enhanced expression of Ngb was achieved by injecting chimeric human Ngb protein, which included the cell membrane-penetrating module of fish Ngb. One-day pretreatment with chimeric Ngb increased immunoreactivity levels of Ngb two-fold in mouse RGCs and increased the number of surviving RGCs three-fold by 14 days after optic nerve injury compared with vehicle controls. Furthermore, in the mouse retinas showing enhanced Ngb expression, several regenerating central optic axons exhibited outgrowth and were found to pass through the nerve crush site 14 days after nerve injury. No such regenerating optic axons were observed in the control mouse optic nerve during the same time frame. The data obtained from in vivo experiments strongly indicate that mammalian Ngb has neuroprotective and neuroregenerative properties.

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Upregulation of Leukemia Inhibitory Factor (LIF) during the Early Stage of Optic Nerve Regeneration in Zebrafish

Cited by 29 publications

References 59 publications

Overexpression of the monocyte chemokine CCL2 in dorsal root ganglion neurons causes a conditioning-like increase in neurite outgrowth and does so via a STAT3 dependent mechanism

Overexpression of the monocyte chemokine CCL2 in dorsal root ganglion neurons causes a conditioning-like increase in neurite outgrowth and does so via a STAT3 dependent mechanism

Complementary research models and methods to study axonal regeneration in the vertebrate retinofugal system

A novel function of neuroglobin for neuroregeneration in mice after optic nerve injury

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