Müller cells derived neurotrophin-3 inhibits hypoxia-induced photoreceptor apoptosis via the TrkC/ERK pathway
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Neurotrophin-3 (NT-3), a neurotrophic factor that mainly binds to the tyrosine kinase C (trkC) receptor, has been shown to play a crucial role in proliferation, differentiation, and survival. However, the role of NT-3 in the hypoxia-induced retinopathy has not been investigated extensively. Here, we created a model of hypoxia (1% O2) in vitro and found that hypoxia promoted the apoptosis of mouse cone photoreceptor-derived 661W cells, increased the expression of TrkC and cleaved caspase-3. In contrast, the hypoxia-mediated 661W cell apoptosis was markedly alleviated by co-culturing with primary mouse Müller cells. Further mechanism studies revealed that hypoxia increased the synthesis and secretion of NT-3 by Müller cells, and exogenous NT-3 stimulation increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 by binding to TrkC in 661W cells. Besides, both siRNA knockdown of TrkC expression and incubation with an ERK-specific inhibitor PD98059 triggered apoptosis in hypoxic 661W cells. Altogether, these data suggest that NT-3 originating from Müller cells protects photoreceptors from hypoxia-induced apoptosis through a TrkC/ERK-dependent pathway. Our findings may facilitate future studies on the therapeutic implications of NT-3 in the treatment of hypoxia-relevant retinal diseases.
KeywordsNeurotrophin-3 Photoreceptor apoptosis Tyrosine kinase C Müller cells Hypoxia
This study was supported by Grants from National Natural Science Foundation of China (Nos. 81670861, 81800826).
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Conflict of interest
The authors have no conflict of interest to report.
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