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.
Highlights
Injury to the central nervous system (CNS) causes the release of endogenous neuroprotective factors
The reduction in the number of ganglion cells was paralleled by an increase in the expression of GFAP, a marker for retinal damage, in the Muller glial cells (Figure 1A). These results indicate that intravitreal injections of 100 mM N-Methyl-D-aspartic acid (NMDA) induce rapid death of retinal ganglion cells in adult mice
We found that blocking endogenous bone morphogenetic protein (BMP) signaling with the combination of DM and noggin led to a further decline in the number of surviving ganglion cells after 10 mM NMDA treatment (Figure 6 A–B)
Summary
Injury to the central nervous system (CNS) causes the release of endogenous neuroprotective factors. Photoreceptors near the site of mechanical injury are protected against lightinduced death in rat retinas [1] by the up-regulation of fibroblast growth factor 2 (FGF2) and ciliary neurotrophic factor (CNTF) [2,3]. Genetic models of retinal degeneration show increased FGF2 and leukemia inhibitory factor (LIF) expression [4,5]. The endogenous increase in expression of these factors provides a degree of neuroprotection, treatment of the retina with exogenous neurotrophic factors can further potentiate neuronal survival in retinal damage. Intravitreal delivery of LIF, CNTF, brain-derived neurotrophic factor (BDNF), or FGF2 promotes survival of photoreceptors after light damage or inherited retinal degeneration, and protects retinal ganglion cells after ischemic injury [6,7,8,9,10]. Smad1/5/8 forms a complex with Smad, which translocates to the nucleus to regulate target gene transcription
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