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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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Regenerative capacity of Müller glial cells mediated by TrkB signalling.(a, b) Treatment with BDNF (100 ng ml−1 for 1–2 days) induced expression of nestin (a) and Mash1 (b) in cultured Müller cells from WT but not TrkBGFAP KO mice. (c, d) Expression of Hes1 and Mash1 (c) and CaMKII (d) in BDNF-treated Müller cells from WT (white bar) and TrkBGFAP KO (black bar) mice. Note the upregulation of CaMKIIδ and Mash1 in WT but not TrkBGFAP KO Müller cells. Data are shown as the mean+s.e.m. (n=4). *P<0.01. (e, f) Treatment with platelet-derived growth factor (PDGF; 50 ng ml−1 for 24 h) induced expression of nestin (e) and Mash1 (f) in cultured Müller cells from WT and TrkBGFAP KO mice. Scale bars, 150 μm (a, e) and 50 μm (b, f).
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f6: Regenerative capacity of Müller glial cells mediated by TrkB signalling.(a, b) Treatment with BDNF (100 ng ml−1 for 1–2 days) induced expression of nestin (a) and Mash1 (b) in cultured Müller cells from WT but not TrkBGFAP KO mice. (c, d) Expression of Hes1 and Mash1 (c) and CaMKII (d) in BDNF-treated Müller cells from WT (white bar) and TrkBGFAP KO (black bar) mice. Note the upregulation of CaMKIIδ and Mash1 in WT but not TrkBGFAP KO Müller cells. Data are shown as the mean+s.e.m. (n=4). *P<0.01. (e, f) Treatment with platelet-derived growth factor (PDGF; 50 ng ml−1 for 24 h) induced expression of nestin (e) and Mash1 (f) in cultured Müller cells from WT and TrkBGFAP KO mice. Scale bars, 150 μm (a, e) and 50 μm (b, f).

Mentions: We further examined the effects of BDNF on cultured Müller cells and found increased nestin expression, a neural stem/progenitor cell marker, in WT but not in TrkBGFAP KO Müller cells (Fig. 6a). When neural stem cells are induced to differentiate into the neurogenic pathway, Mash1, a proneural gene, is derepressed through a signalling cascade that depends on expression of the calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ)3132. In the retina, Mash1 is involved in the generation of bipolar cells and photoreceptors from progenitor cells3334. A previous study showed that CaMKIIδ mediates the phosphorylation of Hes1, which is required for Mash1 activation31. As BDNF can stimulate CaMKII through TrkB16, we next examined whether BDNF regulates this pathway in neural regeneration. We found that BDNF increased Mash1 levels in WT but not in TrkBGFAP KO Müller cells, and the subsequent quantitative analysis revealed that BDNF had no effect on Hes1 expression (Fig. 6b,c). In addition, BDNF significantly increased the expression level of CaMKIIδ but not CaMKIIα, CaMKIIβ or CaMKIIγ in WT Müller cells (Fig. 6d). The BDNF-induced increase of CaMKIIδ was not detected in TrkBGFAP KO Müller cells (Fig. 6d). In contrast, platelet-derived growth factor, which can also activate CaMKII (ref. 31), increased nestin and Mash1 expression in both WT and TrkBGFAP KO Müller cells (Fig. 6e,f). These results suggest that BDNF signalling through TrkB stimulates the CaMKIIδ-Mash1 pathway, which induces the potential capacity of Müller glia as intrinsic retinal progenitor cells.


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)

Regenerative capacity of Müller glial cells mediated by TrkB signalling.(a, b) Treatment with BDNF (100 ng ml−1 for 1–2 days) induced expression of nestin (a) and Mash1 (b) in cultured Müller cells from WT but not TrkBGFAP KO mice. (c, d) Expression of Hes1 and Mash1 (c) and CaMKII (d) in BDNF-treated Müller cells from WT (white bar) and TrkBGFAP KO (black bar) mice. Note the upregulation of CaMKIIδ and Mash1 in WT but not TrkBGFAP KO Müller cells. Data are shown as the mean+s.e.m. (n=4). *P<0.01. (e, f) Treatment with platelet-derived growth factor (PDGF; 50 ng ml−1 for 24 h) induced expression of nestin (e) and Mash1 (f) in cultured Müller cells from WT and TrkBGFAP KO mice. Scale bars, 150 μm (a, e) and 50 μm (b, f).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Regenerative capacity of Müller glial cells mediated by TrkB signalling.(a, b) Treatment with BDNF (100 ng ml−1 for 1–2 days) induced expression of nestin (a) and Mash1 (b) in cultured Müller cells from WT but not TrkBGFAP KO mice. (c, d) Expression of Hes1 and Mash1 (c) and CaMKII (d) in BDNF-treated Müller cells from WT (white bar) and TrkBGFAP KO (black bar) mice. Note the upregulation of CaMKIIδ and Mash1 in WT but not TrkBGFAP KO Müller cells. Data are shown as the mean+s.e.m. (n=4). *P<0.01. (e, f) Treatment with platelet-derived growth factor (PDGF; 50 ng ml−1 for 24 h) induced expression of nestin (e) and Mash1 (f) in cultured Müller cells from WT and TrkBGFAP KO mice. Scale bars, 150 μm (a, e) and 50 μm (b, f).
Mentions: We further examined the effects of BDNF on cultured Müller cells and found increased nestin expression, a neural stem/progenitor cell marker, in WT but not in TrkBGFAP KO Müller cells (Fig. 6a). When neural stem cells are induced to differentiate into the neurogenic pathway, Mash1, a proneural gene, is derepressed through a signalling cascade that depends on expression of the calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ)3132. In the retina, Mash1 is involved in the generation of bipolar cells and photoreceptors from progenitor cells3334. A previous study showed that CaMKIIδ mediates the phosphorylation of Hes1, which is required for Mash1 activation31. As BDNF can stimulate CaMKII through TrkB16, we next examined whether BDNF regulates this pathway in neural regeneration. We found that BDNF increased Mash1 levels in WT but not in TrkBGFAP KO Müller cells, and the subsequent quantitative analysis revealed that BDNF had no effect on Hes1 expression (Fig. 6b,c). In addition, BDNF significantly increased the expression level of CaMKIIδ but not CaMKIIα, CaMKIIβ or CaMKIIγ in WT Müller cells (Fig. 6d). The BDNF-induced increase of CaMKIIδ was not detected in TrkBGFAP KO Müller cells (Fig. 6d). In contrast, platelet-derived growth factor, which can also activate CaMKII (ref. 31), increased nestin and Mash1 expression in both WT and TrkBGFAP KO Müller cells (Fig. 6e,f). These results suggest that BDNF signalling through TrkB stimulates the CaMKIIδ-Mash1 pathway, which induces the potential capacity of Müller glia as intrinsic retinal progenitor cells.

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