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Activation of BMP-Smad1/5/8 signaling promotes survival of retinal ganglion cells after damage in vivo.

Ueki Y, Reh TA - PLoS ONE (2012)

Bottom Line: During this period, BMP2, -4 and -7 were upregulated, leading to phosphorylation of the downstream effector, Smad1/5/8 in the inner retina, including in retinal ganglion cells.Co-injection of BMP inhibitors with NMDA effectively blocked the damage-induced BMP-Smad1/5/8 activation and led to further cell death of retinal ganglion cells, when compared with NMDA injection alone.Moreover, treatment of the retina with exogenous BMP4 along with NMDA damage led to a significant rescue of retinal ganglion cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Structure, University of Washington, Seattle, Washington, United States of America.

ABSTRACT
While the essential role of bone morphogenetic protein (BMP) signaling in nervous system development is well established, its function in the adult CNS is poorly understood. We investigated the role of BMP signaling in the adult mouse retina following damage in vivo. Intravitreal injection of N-methyl-D-aspartic acid (NMDA) induced extensive retinal ganglion cell death by 2 days. During this period, BMP2, -4 and -7 were upregulated, leading to phosphorylation of the downstream effector, Smad1/5/8 in the inner retina, including in retinal ganglion cells. Expression of Inhibitor of differentiation 1 (Id1; a known BMP-Smad1/5/8 target) was also upregulated in the retina. This activation of BMP-Smad1/5/8 signaling was also observed following light damage, suggesting that it is a general response to retinal injuries. Co-injection of BMP inhibitors with NMDA effectively blocked the damage-induced BMP-Smad1/5/8 activation and led to further cell death of retinal ganglion cells, when compared with NMDA injection alone. Moreover, treatment of the retina with exogenous BMP4 along with NMDA damage led to a significant rescue of retinal ganglion cells. These data demonstrate that BMP-Smad1/5/8 signaling is neuroprotective for retinal ganglion cells after damage, and suggest that stimulation of this pathway can serve as a potential target for neuroprotective therapies in retinal ganglion cell diseases, such as glaucoma.

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BMP-Smad1/5/8 signaling is activated in the retina after light damage.A. Exposure to bright light (light damage; LD) is known to induce a significant loss of photoreceptor cells in the ONL. Two days after 8 hrs of LD, there was strong increase in GFAP expression, suggesting the retina was under stress. Smad1/5/8 activation (pSmad 1/5/8) was also observed in retinal ganglion cells and cells in the INL. ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganclion cell layer. Scale bars: 50 µm. B. 8 hrs of LD induced Id1 expression and this was blocked by injection of the BMP inhibitor, DM. Scale bar: 50 µm. C. Representative Western blot showing the level of Id1 expression after the indicated treatments. D. Id1 expression was induced by LD (3.3 fold increase compared to NT), and the expression was effectively blocked by injection of DM along with LD. The level of Id1 expression was normalized to beta-actin. Y axis shows an arbitrary value. *p<0.05 (t-test; n =  at least 3 retinas per treatment). Images shown in A and B are representative of at least 3 animals per each treatment group.
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pone-0038690-g004: BMP-Smad1/5/8 signaling is activated in the retina after light damage.A. Exposure to bright light (light damage; LD) is known to induce a significant loss of photoreceptor cells in the ONL. Two days after 8 hrs of LD, there was strong increase in GFAP expression, suggesting the retina was under stress. Smad1/5/8 activation (pSmad 1/5/8) was also observed in retinal ganglion cells and cells in the INL. ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganclion cell layer. Scale bars: 50 µm. B. 8 hrs of LD induced Id1 expression and this was blocked by injection of the BMP inhibitor, DM. Scale bar: 50 µm. C. Representative Western blot showing the level of Id1 expression after the indicated treatments. D. Id1 expression was induced by LD (3.3 fold increase compared to NT), and the expression was effectively blocked by injection of DM along with LD. The level of Id1 expression was normalized to beta-actin. Y axis shows an arbitrary value. *p<0.05 (t-test; n =  at least 3 retinas per treatment). Images shown in A and B are representative of at least 3 animals per each treatment group.

Mentions: To determine whether the activation of BMP signaling in the inner retina after NMDA damage is specific to this type of retinal injury, or alternatively is a more general response, we also carried out a series of light damage experiments. Albino mice were exposed to intense light for 8 hrs to induce rod photoreceptor loss. As shown in Figure 4A, light damage caused an increase in pSmad1/5/8 at both 1 and 2 days after exposure. The increase in the number and intensity of pSmad1/5/8 labeled cells paralleled the level of GFAP expression in the Müller glia. As in the NMDA damaged retinas, the pSmad1/5/8 labeled cells were found in both the inner nuclear layer and the ganglion cell layer. There was also a 3.3-fold increase in Id1 expression in the Müller glia after light damage, and this effect could be blocked by a co-injection of DM (Figure 4B–D). The effects of light damage on Id1 expression and its inhibition by DM were observed in sections (Figure 4B) and by Western blot (Figure 4C–D).


Activation of BMP-Smad1/5/8 signaling promotes survival of retinal ganglion cells after damage in vivo.

Ueki Y, Reh TA - PLoS ONE (2012)

BMP-Smad1/5/8 signaling is activated in the retina after light damage.A. Exposure to bright light (light damage; LD) is known to induce a significant loss of photoreceptor cells in the ONL. Two days after 8 hrs of LD, there was strong increase in GFAP expression, suggesting the retina was under stress. Smad1/5/8 activation (pSmad 1/5/8) was also observed in retinal ganglion cells and cells in the INL. ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganclion cell layer. Scale bars: 50 µm. B. 8 hrs of LD induced Id1 expression and this was blocked by injection of the BMP inhibitor, DM. Scale bar: 50 µm. C. Representative Western blot showing the level of Id1 expression after the indicated treatments. D. Id1 expression was induced by LD (3.3 fold increase compared to NT), and the expression was effectively blocked by injection of DM along with LD. The level of Id1 expression was normalized to beta-actin. Y axis shows an arbitrary value. *p<0.05 (t-test; n =  at least 3 retinas per treatment). Images shown in A and B are representative of at least 3 animals per each treatment group.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3368846&req=5

pone-0038690-g004: BMP-Smad1/5/8 signaling is activated in the retina after light damage.A. Exposure to bright light (light damage; LD) is known to induce a significant loss of photoreceptor cells in the ONL. Two days after 8 hrs of LD, there was strong increase in GFAP expression, suggesting the retina was under stress. Smad1/5/8 activation (pSmad 1/5/8) was also observed in retinal ganglion cells and cells in the INL. ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganclion cell layer. Scale bars: 50 µm. B. 8 hrs of LD induced Id1 expression and this was blocked by injection of the BMP inhibitor, DM. Scale bar: 50 µm. C. Representative Western blot showing the level of Id1 expression after the indicated treatments. D. Id1 expression was induced by LD (3.3 fold increase compared to NT), and the expression was effectively blocked by injection of DM along with LD. The level of Id1 expression was normalized to beta-actin. Y axis shows an arbitrary value. *p<0.05 (t-test; n =  at least 3 retinas per treatment). Images shown in A and B are representative of at least 3 animals per each treatment group.
Mentions: To determine whether the activation of BMP signaling in the inner retina after NMDA damage is specific to this type of retinal injury, or alternatively is a more general response, we also carried out a series of light damage experiments. Albino mice were exposed to intense light for 8 hrs to induce rod photoreceptor loss. As shown in Figure 4A, light damage caused an increase in pSmad1/5/8 at both 1 and 2 days after exposure. The increase in the number and intensity of pSmad1/5/8 labeled cells paralleled the level of GFAP expression in the Müller glia. As in the NMDA damaged retinas, the pSmad1/5/8 labeled cells were found in both the inner nuclear layer and the ganglion cell layer. There was also a 3.3-fold increase in Id1 expression in the Müller glia after light damage, and this effect could be blocked by a co-injection of DM (Figure 4B–D). The effects of light damage on Id1 expression and its inhibition by DM were observed in sections (Figure 4B) and by Western blot (Figure 4C–D).

Bottom Line: During this period, BMP2, -4 and -7 were upregulated, leading to phosphorylation of the downstream effector, Smad1/5/8 in the inner retina, including in retinal ganglion cells.Co-injection of BMP inhibitors with NMDA effectively blocked the damage-induced BMP-Smad1/5/8 activation and led to further cell death of retinal ganglion cells, when compared with NMDA injection alone.Moreover, treatment of the retina with exogenous BMP4 along with NMDA damage led to a significant rescue of retinal ganglion cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Structure, University of Washington, Seattle, Washington, United States of America.

ABSTRACT
While the essential role of bone morphogenetic protein (BMP) signaling in nervous system development is well established, its function in the adult CNS is poorly understood. We investigated the role of BMP signaling in the adult mouse retina following damage in vivo. Intravitreal injection of N-methyl-D-aspartic acid (NMDA) induced extensive retinal ganglion cell death by 2 days. During this period, BMP2, -4 and -7 were upregulated, leading to phosphorylation of the downstream effector, Smad1/5/8 in the inner retina, including in retinal ganglion cells. Expression of Inhibitor of differentiation 1 (Id1; a known BMP-Smad1/5/8 target) was also upregulated in the retina. This activation of BMP-Smad1/5/8 signaling was also observed following light damage, suggesting that it is a general response to retinal injuries. Co-injection of BMP inhibitors with NMDA effectively blocked the damage-induced BMP-Smad1/5/8 activation and led to further cell death of retinal ganglion cells, when compared with NMDA injection alone. Moreover, treatment of the retina with exogenous BMP4 along with NMDA damage led to a significant rescue of retinal ganglion cells. These data demonstrate that BMP-Smad1/5/8 signaling is neuroprotective for retinal ganglion cells after damage, and suggest that stimulation of this pathway can serve as a potential target for neuroprotective therapies in retinal ganglion cell diseases, such as glaucoma.

Show MeSH
Related in: MedlinePlus