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Glia- and neuron-specific functions of TrkB signalling during retinal degeneration and regeneration.

Harada C, Guo X, Namekata K, Kimura A, Nakamura K, Tanaka K, Parada LF, Harada T - Nat Commun (2011)

Bottom Line: Furthermore in TrkB(GFAP) knockout mice, BDNF did not prevent photoreceptor degeneration and failed to stimulate Müller glial cell proliferation and expression of neural markers in the degenerating retina.These results demonstrate that BDNF signalling in glia has important roles in neural protection and regeneration, particularly in conversion of Müller glia to photoreceptors.In addition, our genetic models provide a system in which glia- and neuron-specific gene functions can be tested in central nervous system tissues in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo 183-8526, Japan.

ABSTRACT
Glia, the support cells of the central nervous system, have recently attracted considerable attention both as mediators of neural cell survival and as sources of neural regeneration. To further elucidate the role of glial and neural cells in neurodegeneration, we generated TrkB(GFAP) and TrkB(c-kit) knockout mice in which TrkB, a receptor for brain-derived neurotrophic factor (BDNF), is deleted in retinal glia or inner retinal neurons, respectively. Here, we show that the extent of glutamate-induced retinal degeneration was similar in these two mutant mice. Furthermore in TrkB(GFAP) knockout mice, BDNF did not prevent photoreceptor degeneration and failed to stimulate Müller glial cell proliferation and expression of neural markers in the degenerating retina. These results demonstrate that BDNF signalling in glia has important roles in neural protection and regeneration, particularly in conversion of Müller glia to photoreceptors. In addition, our genetic models provide a system in which glia- and neuron-specific gene functions can be tested in central nervous system tissues in vivo.

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Similar susceptibility to glutamate neurotoxicity in TrkBc-kit KO and TrkBGFAP KO retinas.(a) Immunohistochemical analysis of mouse retinal explants from WT, TrkBc-kit KO and TrkBGFAP KO mice stained with an anti-NeuN antibody. Explants were untreated (control) or treated with 5 mM glutamate for 1 h. Scale bar, 50 μm. (b) Quantification of NeuN-positive cells in the GCL. Data are shown as the mean+s.e.m. (n=6). *P<0.01. GCL, ganglion cell layer; INL, inner nuclear layer.
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f2: Similar susceptibility to glutamate neurotoxicity in TrkBc-kit KO and TrkBGFAP KO retinas.(a) Immunohistochemical analysis of mouse retinal explants from WT, TrkBc-kit KO and TrkBGFAP KO mice stained with an anti-NeuN antibody. Explants were untreated (control) or treated with 5 mM glutamate for 1 h. Scale bar, 50 μm. (b) Quantification of NeuN-positive cells in the GCL. Data are shown as the mean+s.e.m. (n=6). *P<0.01. GCL, ganglion cell layer; INL, inner nuclear layer.

Mentions: Neurotrophins prevent RGC death from glutamate neurotoxicity26. As RGCs express TrkB receptors, we compared the roles of TrkB signalling in RGCs and Müller glia in BDNF-dependent neuroprotection to determine the direct and indirect effects, respectively. For this purpose, we prepared retinal explants from WT, TrkBc-kit KO and TrkBGFAP KO mice (Fig. 2a). The WT retinal explants stimulated with 5 mM glutamate for 1 h showed a decrease in the number of NeuN-positive neurons in the ganglion cell layer (GCL) compared with the untreated control explants (Fig. 2a,b). As expected, the same treatment significantly decreased the number of surviving RGCs in the TrkBc-kit KO mouse retina. We predicted milder RGC degeneration in the TrkBGFAP KO compared with the TrkBc-kit KO mouse retina; however, RGC loss was as severe as that observed in the TrkBc-kit KO mouse retina (Fig. 2a,b). These results suggest that, at least under our experimental conditions, the indirect protective effect of BDNF by Müller glia is as powerful as the direct effect through TrkB in RGCs.


Glia- and neuron-specific functions of TrkB signalling during retinal degeneration and regeneration.

Harada C, Guo X, Namekata K, Kimura A, Nakamura K, Tanaka K, Parada LF, Harada T - Nat Commun (2011)

Similar susceptibility to glutamate neurotoxicity in TrkBc-kit KO and TrkBGFAP KO retinas.(a) Immunohistochemical analysis of mouse retinal explants from WT, TrkBc-kit KO and TrkBGFAP KO mice stained with an anti-NeuN antibody. Explants were untreated (control) or treated with 5 mM glutamate for 1 h. Scale bar, 50 μm. (b) Quantification of NeuN-positive cells in the GCL. Data are shown as the mean+s.e.m. (n=6). *P<0.01. GCL, ganglion cell layer; INL, inner nuclear layer.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105320&req=5

f2: Similar susceptibility to glutamate neurotoxicity in TrkBc-kit KO and TrkBGFAP KO retinas.(a) Immunohistochemical analysis of mouse retinal explants from WT, TrkBc-kit KO and TrkBGFAP KO mice stained with an anti-NeuN antibody. Explants were untreated (control) or treated with 5 mM glutamate for 1 h. Scale bar, 50 μm. (b) Quantification of NeuN-positive cells in the GCL. Data are shown as the mean+s.e.m. (n=6). *P<0.01. GCL, ganglion cell layer; INL, inner nuclear layer.
Mentions: Neurotrophins prevent RGC death from glutamate neurotoxicity26. As RGCs express TrkB receptors, we compared the roles of TrkB signalling in RGCs and Müller glia in BDNF-dependent neuroprotection to determine the direct and indirect effects, respectively. For this purpose, we prepared retinal explants from WT, TrkBc-kit KO and TrkBGFAP KO mice (Fig. 2a). The WT retinal explants stimulated with 5 mM glutamate for 1 h showed a decrease in the number of NeuN-positive neurons in the ganglion cell layer (GCL) compared with the untreated control explants (Fig. 2a,b). As expected, the same treatment significantly decreased the number of surviving RGCs in the TrkBc-kit KO mouse retina. We predicted milder RGC degeneration in the TrkBGFAP KO compared with the TrkBc-kit KO mouse retina; however, RGC loss was as severe as that observed in the TrkBc-kit KO mouse retina (Fig. 2a,b). These results suggest that, at least under our experimental conditions, the indirect protective effect of BDNF by Müller glia is as powerful as the direct effect through TrkB in RGCs.

Bottom Line: Furthermore in TrkB(GFAP) knockout mice, BDNF did not prevent photoreceptor degeneration and failed to stimulate Müller glial cell proliferation and expression of neural markers in the degenerating retina.These results demonstrate that BDNF signalling in glia has important roles in neural protection and regeneration, particularly in conversion of Müller glia to photoreceptors.In addition, our genetic models provide a system in which glia- and neuron-specific gene functions can be tested in central nervous system tissues in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo 183-8526, Japan.

ABSTRACT
Glia, the support cells of the central nervous system, have recently attracted considerable attention both as mediators of neural cell survival and as sources of neural regeneration. To further elucidate the role of glial and neural cells in neurodegeneration, we generated TrkB(GFAP) and TrkB(c-kit) knockout mice in which TrkB, a receptor for brain-derived neurotrophic factor (BDNF), is deleted in retinal glia or inner retinal neurons, respectively. Here, we show that the extent of glutamate-induced retinal degeneration was similar in these two mutant mice. Furthermore in TrkB(GFAP) knockout mice, BDNF did not prevent photoreceptor degeneration and failed to stimulate Müller glial cell proliferation and expression of neural markers in the degenerating retina. These results demonstrate that BDNF signalling in glia has important roles in neural protection and regeneration, particularly in conversion of Müller glia to photoreceptors. In addition, our genetic models provide a system in which glia- and neuron-specific gene functions can be tested in central nervous system tissues in vivo.

Show MeSH
Related in: MedlinePlus