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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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Accelerated photoreceptor degeneration in TrkBGFAP KO mice.(a) Animal protocols for MNU-induced photoreceptor degeneration. MNU was injected intraperitoneally (i.p.) into WT and TrkBGFAP KO mice at the concentration of 0, 7.5, 15 or 60 mg kg−1. PBS or BDNF (1 μg μl−1) was intraocularly injected at day 0, 2 and 4, and the animals were killed at day 7 after MNU treatment. (b) Representative photomicrographs of PBS- or BDNF-treated retinas from WT and TrkBGFAP KO mice administered with various concentrations of MNU. Scale bar, 50 μm. (c, d) Quantitative analysis of the thickness of the ONL (c) and the IRL (d) in PBS (white bar)- or BDNF (black bar)-treated retinas. Data are shown as the mean s.e.m. (n=4). *P<0.05. IRL, inner retinal layer; ONL, outer nuclear layer.
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f4: Accelerated photoreceptor degeneration in TrkBGFAP KO mice.(a) Animal protocols for MNU-induced photoreceptor degeneration. MNU was injected intraperitoneally (i.p.) into WT and TrkBGFAP KO mice at the concentration of 0, 7.5, 15 or 60 mg kg−1. PBS or BDNF (1 μg μl−1) was intraocularly injected at day 0, 2 and 4, and the animals were killed at day 7 after MNU treatment. (b) Representative photomicrographs of PBS- or BDNF-treated retinas from WT and TrkBGFAP KO mice administered with various concentrations of MNU. Scale bar, 50 μm. (c, d) Quantitative analysis of the thickness of the ONL (c) and the IRL (d) in PBS (white bar)- or BDNF (black bar)-treated retinas. Data are shown as the mean s.e.m. (n=4). *P<0.05. IRL, inner retinal layer; ONL, outer nuclear layer.

Mentions: Various trophic factors rescue photoreceptors during retinal degeneration272829. As photoreceptors do not express a high level of neurotrophin receptors, the indirect glia-mediated rescue pathway may be more important for photoreceptors than for other cell types, including RGCs121318. To further elucidate the effect of the glia-neuron network in neuroprotection in vivo, we used a second animal disease model, N-methyl-N-nitrosourea (MNU)-induced photoreceptor degeneration (Fig. 4a). MNU is an alkylating agent that causes DNA methylation and activates caspases, leading to photoreceptor apoptosis in various animal species30. In WT mice, 15 mg kg−1 MNU decreased the thickness of the outer nuclear layer (ONL), but intravitreous injection of BDNF partially rescued the photoreceptor loss (Fig. 4b,c). However, in TrkBGFAP KO mice, 7.5 mg kg−1 MNU resulted in an ∼50% loss of the ONL, which was significantly greater than the loss in WT retinas, and BDNF failed to induce photoreceptor survival against any doses of MNU (Fig. 4b,c). The protective effect of BDNF in WT mice diminished in the presence of a higher dose of MNU (60 mg kg−1); this dose completely abolished the ONL but left the inner retinal layer (IRL) intact (Fig. 4b,d). In contrast, the same dose of MNU applied to TrkBGFAP KO mice induced considerable loss of the IRL as well as the removal of the ONL (Fig. 4b,d). These in vivo data suggest that glial TrkB signalling has a pivotal role in the protection of surrounding neurons.


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)

Accelerated photoreceptor degeneration in TrkBGFAP KO mice.(a) Animal protocols for MNU-induced photoreceptor degeneration. MNU was injected intraperitoneally (i.p.) into WT and TrkBGFAP KO mice at the concentration of 0, 7.5, 15 or 60 mg kg−1. PBS or BDNF (1 μg μl−1) was intraocularly injected at day 0, 2 and 4, and the animals were killed at day 7 after MNU treatment. (b) Representative photomicrographs of PBS- or BDNF-treated retinas from WT and TrkBGFAP KO mice administered with various concentrations of MNU. Scale bar, 50 μm. (c, d) Quantitative analysis of the thickness of the ONL (c) and the IRL (d) in PBS (white bar)- or BDNF (black bar)-treated retinas. Data are shown as the mean s.e.m. (n=4). *P<0.05. IRL, inner retinal layer; ONL, outer nuclear layer.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Accelerated photoreceptor degeneration in TrkBGFAP KO mice.(a) Animal protocols for MNU-induced photoreceptor degeneration. MNU was injected intraperitoneally (i.p.) into WT and TrkBGFAP KO mice at the concentration of 0, 7.5, 15 or 60 mg kg−1. PBS or BDNF (1 μg μl−1) was intraocularly injected at day 0, 2 and 4, and the animals were killed at day 7 after MNU treatment. (b) Representative photomicrographs of PBS- or BDNF-treated retinas from WT and TrkBGFAP KO mice administered with various concentrations of MNU. Scale bar, 50 μm. (c, d) Quantitative analysis of the thickness of the ONL (c) and the IRL (d) in PBS (white bar)- or BDNF (black bar)-treated retinas. Data are shown as the mean s.e.m. (n=4). *P<0.05. IRL, inner retinal layer; ONL, outer nuclear layer.
Mentions: Various trophic factors rescue photoreceptors during retinal degeneration272829. As photoreceptors do not express a high level of neurotrophin receptors, the indirect glia-mediated rescue pathway may be more important for photoreceptors than for other cell types, including RGCs121318. To further elucidate the effect of the glia-neuron network in neuroprotection in vivo, we used a second animal disease model, N-methyl-N-nitrosourea (MNU)-induced photoreceptor degeneration (Fig. 4a). MNU is an alkylating agent that causes DNA methylation and activates caspases, leading to photoreceptor apoptosis in various animal species30. In WT mice, 15 mg kg−1 MNU decreased the thickness of the outer nuclear layer (ONL), but intravitreous injection of BDNF partially rescued the photoreceptor loss (Fig. 4b,c). However, in TrkBGFAP KO mice, 7.5 mg kg−1 MNU resulted in an ∼50% loss of the ONL, which was significantly greater than the loss in WT retinas, and BDNF failed to induce photoreceptor survival against any doses of MNU (Fig. 4b,c). The protective effect of BDNF in WT mice diminished in the presence of a higher dose of MNU (60 mg kg−1); this dose completely abolished the ONL but left the inner retinal layer (IRL) intact (Fig. 4b,d). In contrast, the same dose of MNU applied to TrkBGFAP KO mice induced considerable loss of the IRL as well as the removal of the ONL (Fig. 4b,d). These in vivo data suggest that glial TrkB signalling has a pivotal role in the protection of surrounding neurons.

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