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Active mechanistic target of rapamycin plays an ancillary rather than essential role in zebrafish CNS axon regeneration.

Diekmann H, Kalbhen P, Fischer D - Front Cell Neurosci (2015)

Bottom Line: Remarkably, regulation of mTOR activity after optic nerve injury in zebrafish is fundamentally different compared to mammals.Moreover, inhibition of mTOR using rapamycin significantly reduced axon regeneration in vivo and compromised functional recovery after optic nerve injury.Therefore, axotomy-induced mTOR activity is involved in CNS axon regeneration in zebrafish similar to mammals, although it plays an ancillary rather than essential role in this regeneration-competent species.

View Article: PubMed Central - PubMed

Affiliation: Division of Experimental Neurology, Department of Neurology, Heinrich-Heine-University of Düsseldorf Düsseldorf, Germany.

ABSTRACT
The developmental decrease of the intrinsic regenerative ability of the mammalian central nervous system (CNS) is associated with reduced activity of mechanistic target of rapamycin (mTOR) in mature neurons such as retinal ganglion cells (RGCs). While mTOR activity is further decreased upon axonal injury, maintenance of its pre-injury level, for instance by genetic deletion of the phosphatase and tensin homolog (PTEN), markedly promotes axon regeneration in mammals. The current study now addressed the question whether active mTOR might generally play a central role in axon regeneration by analyzing its requirement in regeneration-competent zebrafish. Remarkably, regulation of mTOR activity after optic nerve injury in zebrafish is fundamentally different compared to mammals. Hardly any activity was detected in naïve RGCs, whereas it was markedly increased upon axotomy in vivo as well as in dissociated cell cultures. After a short burst, mTOR activity was quickly attenuated, which is contrary to the requirements for axon regeneration in mammals. Surprisingly, mTOR activity was not essential for axonal growth per se, but correlated with cytokine- and PTEN inhibitor-induced neurite extension in vitro. Moreover, inhibition of mTOR using rapamycin significantly reduced axon regeneration in vivo and compromised functional recovery after optic nerve injury. Therefore, axotomy-induced mTOR activity is involved in CNS axon regeneration in zebrafish similar to mammals, although it plays an ancillary rather than essential role in this regeneration-competent species.

No MeSH data available.


Related in: MedlinePlus

Schematic showing the ancillary contribution of mTOR activity to axon regeneration in adult zebrafish. (A) Upon optic nerve injury, diverse and prevalently unknown molecular mechanisms (gray arrow) are activated in adult zebrafish RGCs to enable axon growth and functional regeneration. Among others, cytokines such as LIF are released and activate the JAK/STAT and PI3K/AKT/mTOR pathways that contribute to axon regeneration. The initial burst of mTOR activity could then be quickly attenuated by negative feedback loops (red lines). (B) Inhibition of mTOR using rapamycin only partially reduces axon regrowth and compromises functional recovery, suggesting an ancillary rather than essential role of mTOR activity in zebrafish optic nerve regeneration.
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Figure 6: Schematic showing the ancillary contribution of mTOR activity to axon regeneration in adult zebrafish. (A) Upon optic nerve injury, diverse and prevalently unknown molecular mechanisms (gray arrow) are activated in adult zebrafish RGCs to enable axon growth and functional regeneration. Among others, cytokines such as LIF are released and activate the JAK/STAT and PI3K/AKT/mTOR pathways that contribute to axon regeneration. The initial burst of mTOR activity could then be quickly attenuated by negative feedback loops (red lines). (B) Inhibition of mTOR using rapamycin only partially reduces axon regrowth and compromises functional recovery, suggesting an ancillary rather than essential role of mTOR activity in zebrafish optic nerve regeneration.

Mentions: The progression of mTOR activity after optic nerve injury in zebrafish differed significantly from the one in rodents. In retinae from naïve, adult mice, only 10–15% of RGCs contain high levels of phosphorylated S6 and reportedly have the highest probability to regenerate (Duan et al., 2015). This proportion is even further reduced upon optic nerve injury (Park et al., 2008; Leibinger et al., 2012). In contrast, no pS6 staining was observed in RGCs of naïve zebrafish retinae. However, S6 phosphorylation in RGCs was markedly induced in vivo shortly after optic nerve injury as well as in dissociated cell cultures. In addition, prolonged mTOR induction was observed in cholinergic amacrines after an initial lag phase. The activity of mTOR is reportedly controlled by the PI3K/AKT, MAPK/ERK, CDK42/phopholipase D and wnt pathways (Fang et al., 2001, 2003; Ma et al., 2005; Huang and Manning, 2009; Hirose et al., 2014). Interestingly, leukemia inhibitory factor (LIF), a IL6-like cytokine, which reportedly activates the PI3K/AKT/mTOR pathway in rodents (Li et al., 2014), is strongly upregulated in zebrafish RGCs early after axotomy (Ogai et al., 2014) and could potentially contribute to the transient mTOR activation (Figure 6). However, the elucidation of the detailed stimuli involved in activating mTOR after optic nerve injury in zebrafish awaits further investigations.


Active mechanistic target of rapamycin plays an ancillary rather than essential role in zebrafish CNS axon regeneration.

Diekmann H, Kalbhen P, Fischer D - Front Cell Neurosci (2015)

Schematic showing the ancillary contribution of mTOR activity to axon regeneration in adult zebrafish. (A) Upon optic nerve injury, diverse and prevalently unknown molecular mechanisms (gray arrow) are activated in adult zebrafish RGCs to enable axon growth and functional regeneration. Among others, cytokines such as LIF are released and activate the JAK/STAT and PI3K/AKT/mTOR pathways that contribute to axon regeneration. The initial burst of mTOR activity could then be quickly attenuated by negative feedback loops (red lines). (B) Inhibition of mTOR using rapamycin only partially reduces axon regrowth and compromises functional recovery, suggesting an ancillary rather than essential role of mTOR activity in zebrafish optic nerve regeneration.
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Related In: Results  -  Collection

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Figure 6: Schematic showing the ancillary contribution of mTOR activity to axon regeneration in adult zebrafish. (A) Upon optic nerve injury, diverse and prevalently unknown molecular mechanisms (gray arrow) are activated in adult zebrafish RGCs to enable axon growth and functional regeneration. Among others, cytokines such as LIF are released and activate the JAK/STAT and PI3K/AKT/mTOR pathways that contribute to axon regeneration. The initial burst of mTOR activity could then be quickly attenuated by negative feedback loops (red lines). (B) Inhibition of mTOR using rapamycin only partially reduces axon regrowth and compromises functional recovery, suggesting an ancillary rather than essential role of mTOR activity in zebrafish optic nerve regeneration.
Mentions: The progression of mTOR activity after optic nerve injury in zebrafish differed significantly from the one in rodents. In retinae from naïve, adult mice, only 10–15% of RGCs contain high levels of phosphorylated S6 and reportedly have the highest probability to regenerate (Duan et al., 2015). This proportion is even further reduced upon optic nerve injury (Park et al., 2008; Leibinger et al., 2012). In contrast, no pS6 staining was observed in RGCs of naïve zebrafish retinae. However, S6 phosphorylation in RGCs was markedly induced in vivo shortly after optic nerve injury as well as in dissociated cell cultures. In addition, prolonged mTOR induction was observed in cholinergic amacrines after an initial lag phase. The activity of mTOR is reportedly controlled by the PI3K/AKT, MAPK/ERK, CDK42/phopholipase D and wnt pathways (Fang et al., 2001, 2003; Ma et al., 2005; Huang and Manning, 2009; Hirose et al., 2014). Interestingly, leukemia inhibitory factor (LIF), a IL6-like cytokine, which reportedly activates the PI3K/AKT/mTOR pathway in rodents (Li et al., 2014), is strongly upregulated in zebrafish RGCs early after axotomy (Ogai et al., 2014) and could potentially contribute to the transient mTOR activation (Figure 6). However, the elucidation of the detailed stimuli involved in activating mTOR after optic nerve injury in zebrafish awaits further investigations.

Bottom Line: Remarkably, regulation of mTOR activity after optic nerve injury in zebrafish is fundamentally different compared to mammals.Moreover, inhibition of mTOR using rapamycin significantly reduced axon regeneration in vivo and compromised functional recovery after optic nerve injury.Therefore, axotomy-induced mTOR activity is involved in CNS axon regeneration in zebrafish similar to mammals, although it plays an ancillary rather than essential role in this regeneration-competent species.

View Article: PubMed Central - PubMed

Affiliation: Division of Experimental Neurology, Department of Neurology, Heinrich-Heine-University of Düsseldorf Düsseldorf, Germany.

ABSTRACT
The developmental decrease of the intrinsic regenerative ability of the mammalian central nervous system (CNS) is associated with reduced activity of mechanistic target of rapamycin (mTOR) in mature neurons such as retinal ganglion cells (RGCs). While mTOR activity is further decreased upon axonal injury, maintenance of its pre-injury level, for instance by genetic deletion of the phosphatase and tensin homolog (PTEN), markedly promotes axon regeneration in mammals. The current study now addressed the question whether active mTOR might generally play a central role in axon regeneration by analyzing its requirement in regeneration-competent zebrafish. Remarkably, regulation of mTOR activity after optic nerve injury in zebrafish is fundamentally different compared to mammals. Hardly any activity was detected in naïve RGCs, whereas it was markedly increased upon axotomy in vivo as well as in dissociated cell cultures. After a short burst, mTOR activity was quickly attenuated, which is contrary to the requirements for axon regeneration in mammals. Surprisingly, mTOR activity was not essential for axonal growth per se, but correlated with cytokine- and PTEN inhibitor-induced neurite extension in vitro. Moreover, inhibition of mTOR using rapamycin significantly reduced axon regeneration in vivo and compromised functional recovery after optic nerve injury. Therefore, axotomy-induced mTOR activity is involved in CNS axon regeneration in zebrafish similar to mammals, although it plays an ancillary rather than essential role in this regeneration-competent species.

No MeSH data available.


Related in: MedlinePlus