Neg, a nerve growth factor–stimulated gene expressed by fetal neocortical neurons that is downregulated by ethanol

Abstract

Neurotrophins are critical for neuronal development, plasticity, and survival. Ethanol affects these processes. We tested the hypothesis that ethanol inhibits nerve growth factor (NGF)-stimulated gene expression. Dissociated cultures of fetal cortical neurons were treated with NGF and/or ethanol. NGF sustained cell viability and reduced the incidence of terminal uridylated nick-end labeling and pyknosis. Ethanol eliminated these effects and induced neuronal death. Differential display of mRNA showed that one gene fragment (245 bp) was expressed by cells treated with NGF alone; ethanol blocked its expression. This fragment, named neg (nerve growth factor-stimulated, ethanol-depressed gene), has high nucleotide identity with genes from human myeloid cells and murine lymphocytes. Ribonuclease protection assay and in situ hybridization verified NGF upregulation and ethanol antagonism. Thus, ethanol specifically alters the expression of a gene that appears to be involved in NGF-mediated neuroprotection.

Nerve growth factor neuroprotection of ethanol-induced neuronal death in rat cerebral cortex is age dependent

“…Neither the NOND nor the ethanolinduced cell death in fetal cultures is mitigated by concurrent administration of NGF. This lack of protection from ethanol-induced death is similar to the non-response previously reported in primary cultures of cortical neurons taken from fetal tissue (Seabold et al, 1998;Miller et al, 2003;Barclay et al, 2005).…”

“…Ethanol blocks this effect. In other words, NGF fails to prevent the ethanol-induced death of primary cortical neurons (Seabold et al, 1998;Miller et al, 2003;Barclay et al, 2005). Conversely, NGF is protective against ethanol-induced death in cultured septal, hippocampal (Webb et al, 1997), and cerebellar neurons .…”

“…Among the neurotrophins, nerve growth factor (NGF) uniquely prevents the death of primary cultured, fetal cortical neurons (Seabold et al, 1998;Miller et al, 2003). NGF and its receptors, p75 and trkA, are expressed by developing (Cirulli et al, 1997;Conner and Varon, 1997;Dohrman et al, 1997;Seabold et al, 1998;Kwon et al, 2005) and mature cortical neurons (Conner et al, 1992;Pitts and Miller, 1995;2000;Jacobs and Miller, 1999;Miller, 2000;Miller and Pitts, 2000;Bruns and Miller, 2007).…”

“…In contrast, signaling via p75 can activate cell survival or cell death pathways. NGF can be neuroprotective, i.e., it can reduce the amount of cell death in vitro that is normally detected within the first 48 hours of plating (Seabold et al, 1998;Miller et al, 2003). Ethanol blocks this effect.…”

Modeling the Impact of Alcohol on Cortical Development in a Dish: Strategies from Mapping Neural Stem Cell Fate

“…Rodent cell culture models and tumor-derived cell lines also have been used extensively to understand the effects of ethanol on neuronal survival and differentiation, i.e., events that occur during the third trimester. Using these models, we and others, have shown that, in differentiated neural tissue, part of alcohol's neurotoxicity may be caused by the induction of death mechanisms (18)(19)(20)(21), the loss of growth and survival factors (22)(23)(24)(25)(26)(27)(28), alterations in neuronal migration (29), and in neurotransmitters systems (30), among others. Further, in vitro studies found that the state of differentiation of the cells determined the degree of sensitivity to alcohol insult (31,32), confirming in vivo work showing windows of vulnerability that reflected maturation of the neurons (16,33,34).…”