Activation of BMP-Smad1/5/8 Signaling Promotes Survival of Retinal Ganglion Cells after Damage In Vivo

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

Smoothened, Stem Cell Maintenance and Brain Diseases

International audienceThe Smoothened (Smo) receptor is a key transducer of the Sonic Hedgehog (Shh) signaling pathway in the brain. Recent studies in rodents have highlighted its major role in the maintenance of neural stem and progenitor cells in the two main neurogenic niches of the adult brain: the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus in the hippocampus. Smo may also regulate brain responses to various injuries, and its modulation in the primary cilia of brain cells is essential for regulating Shh signals. Recent clinical trials have underlined the therapeutic value of some Smo antagonists for the treatment of Hedgehog-linked medulloblastomas. Here, we review recent findings on the roles of Smo in the adult brain, and unravel research on the clinical implications for the treatment of brain diseases, that are increasingly under investigation