Müller cells derived neurotrophin-3 inhibits hypoxia-induced photoreceptor apoptosis via the TrkC/ERK pathway

Abstract

, 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% O 2 ) 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 Mu ¨ller cells. Further mechanism studies revealed that hypoxia increased the synthesis and secretion of NT-3 by Mu ¨ller 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 Mu ¨ller 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 hypoxiarelevant retinal diseases.

Interleukin-17A attenuates photoreceptor cell apoptosis in streptozotocin-induced diabetic mouse model

“…Müller cells are a major source of neurotrophins, e.g. nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and NT-3 [ 17 , 22 , 23 ]. We then focused on NT-3, which is involved in the survival of photoreceptors.…”

“…It has been reported that TrkC signaling controls the pro-survival effects of NT-3 on photoreceptors, whereas p75 NTR activation via binding to proNT-3 triggers apoptosis [ 17 , 24 ]. Using the normoglycemic and hyperglycemic co-culture systems, respectively, TrkC and p75 NTR expression levels were examined in photoreceptor (661 W) cells.…”

“…TrkC-targeting (siTrkC, 5’-GGACGATGGGAACCTCTTC-3’) and non-targeting siRNA (siNC) were purchased from GenePharma Biotechnology (Shanghai, China). Transfection was performed on Müller cell with Lipofectamine 2000 (Invitrogen, Grand Island, NY) reagent as reported in our previous study [ 17 ].…”

Potential therapeutic strategies for photoreceptor degeneration: the path to restore vision

“…Early attempts to retain neural viability include delivering endogenous or exogenous neurotrophic factors (NTFs) to neural retina tissues [ 108 ], which enhance PR cell survival through several neuroprotective interventions. NTFs consist of neurotrophins (NTs) generally, as well as related molecules, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) [ 109 ], neurotrophin-4/5 (NT-4/5) [ 110 ], glial-derived neurotrophic factor (GDNF) (neurturin, artemin, persephin), the serine protease inhibitor (srpin) family, pigment epithelium-derived factor (PEDF), neuropoietic cytokines (ciliary neurotrophic factor (CNTF)), insulin-like growth factors, and transforming growth factors (TGF) [ 111 , 112 ]. These neurotrophins, which can be released by glial cells, including microglia and macroglia [ 113 , 114 ], are found in photoreceptor segments [ 115 ].…”

Eurycomanone from <i>Eurycoma longifolia</i> Jack upregulates neurotrophin-3 gene expression in ‍retinal Müller cells <i>in vitro</i>

“…(4) Moreover, NT3 produced by Müller cells protects against photoreceptor apoptosis caused by hypoxia-induced oxidative stress in mice. (5) Harada et al demonstrated that light-induced damage promotes the expression of TrkC but not TrkA, TrkB, or p75 NTR in rat photoreceptors. (3) These findings suggest that NT3 may contribute more directly to photoreceptor cell protection compared to NGF or BDNF.…”