The MAPK and PI3K pathways mediate CNTF-induced neuronal survival and process outgrowth in hypothalamic organotypic cultures

Abstract

While collateral sprouting has been shown to occur in a variety of neuronal populations, the factor or factors responsible for mediating the sprouting response remain largely un-defined. There is evidence indicating that ciliary neurotrophic factor (CNTF) may play an important role in promoting neuronal survival and process outgrowth in neuronal phenotypes tested to date. We previously demonstrated that the astrocytic Jak-STAT pathway is necessary to mediate CNTF-induced oxytocinergic (OT) neuronal survival; however, the mechanism (s) of CNTF-mediated process outgrowth remain unknown. Our working hypothesis is that CNTF mediates differential neuroprotective responses via different intracellular signal transduction pathways. In order to test this hypothesis, we utilized stationary hypothalamic organotypic cultures to assess the contribution of the MAPK-ERK and PI3-AKT pathways to OT neuron survival and process outgrowth. Our results demonstrate that the MAPK-ERK½ pathway mediates CNTF-induced neuronal survival. Moreover, we show that inhibition of the p38-, JNK-MAPK, and mTOR pathways prevents loss OT neurons following axotomy. We also provide quantitative evidence indicating that CNTF promotes process outgrowth of OT neurons via the PI3K-AKT pathway. Together, these data indicate that distinct intracellular signaling pathways mediate diverse neuroprotective processes in response to CNTF.

Ciliary neurotrophic factor (CNTF): New facets of an old molecule for treating neurodegenerative and metabolic syndrome pathologies

“…4) [46][47][48]. CNTF induced PI3K/Akt pathway was shown to be important in survival and neurite growth of neuroblastoma cells and responsible for CNTF effect on skeletal muscle glucose uptake [49][50][51]. MAPK-ERK1/2 pathway was demonstrated to play an important role in CNTF induced neuronal survival in stationary hypothalamic cultures [50].…”

“…CNTF induced PI3K/Akt pathway was shown to be important in survival and neurite growth of neuroblastoma cells and responsible for CNTF effect on skeletal muscle glucose uptake [49][50][51]. MAPK-ERK1/2 pathway was demonstrated to play an important role in CNTF induced neuronal survival in stationary hypothalamic cultures [50]. Whereas STAT3 phosphorylation can be regulated by mTOR, CNTF activation of MAPK-ERK1/2 appears to be mediated through JAK2-dependent Ras and Raf activation [52].…”

Ciliary neurotrophic factor-treated astrocyte-conditioned medium increases the intracellular free calcium concentration in rat cortical neurons

“…In brief, following dissociation, the cortical tissue was plated on 75-cm 2 poly-d-lysine-coated culture flasks in Dulbecco's modified Eagle's medium (DMEM)/F12 (1:1) supplemented with 100 µg/ml streptomycin, 100 U/ml penicillin and 10% fetal bovine serum (Gibco, Thermo Fisher Scientific, Inc., Waltham, MA, USA). The cultures were maintained in a humid incubator at 37˚C in 5% CO 2 . After confluence at 7-10 days in vitro (DIV), the cells were agitated at 37˚C at 250 rpm for Immunoassay.…”

“…Ciliary neurotrophic factor (CNTF), a survival factor for chick ciliary neurons (1), is reported to facilitate the survival of several types of neurons such as sympathetic, sensory and motor neurons (2). In addition, it has important roles in triggering neurite outgrowth, preventing neuronal degeneration and attenuating motor deficits (3).…”

Glycitein induces reactive oxygen species‐dependent apoptosis and G0/G1 cell cycle arrest through the MAPK/STAT3/NF‐κB pathway in human gastric cancer cells

“…Furthermore, several reports have shown that ROS are involved in triggering apoptosis signaling in cancer cells including prolonged MAPK activation and inhibition of p-STAT3 and NF-κB(Askvig & Watt, 2015;Zuo et al, 2016). 4a).…”