Peptide-Mediated Protection from Ethanol-Induced Neural Tube Defects

Chen, Shao Yu; Charness, Michael E.; Wilkemeyer, Michael F.; Sulik, Kathleen K.

doi:10.1159/000084528

Cited by 57 publications

(39 citation statements)

References 84 publications

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“…The well known "fetal alcohol syndrome" (FAS) is the result of the exposure of fetuses or neonates to alcohol during a critical period of brain development (Sulik et al, 1981;Goodlett et al, 2005) and is associated with brain damage, cognitive deficits, and craniofacial abnormalities, in both mouse and man (Chen et al, 2005;Sulik, 2005). It is less widely appreciated that similar developmental abnormalities, including neural tube defects, can also be triggered by excessive heat during gestation (Edwards, 2006).…”

Section: Discussionmentioning

confidence: 99%

Alcohol Regulates Gene Expression in Neurons via Activation of Heat Shock Factor 1

Pignataro

Miller²,

Ma³

et al. 2007

J. Neurosci.

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Drinking alcohol causes widespread alterations in gene expression that can result in long-term physiological changes. Although many alcohol-responsive genes (ARGs) have been identified, the mechanisms by which alcohol alters transcription are not well understood. To elucidate these mechanisms, we investigated Gabra4, a neuron-specific gene that is rapidly and robustly activated by alcohol (10 -60 mM), both in vitro and in vivo. Here we show that alcohol can activate elements of the heat shock pathway in mouse cortical neurons to enhance the expression of Gabra4 and other ARGs. The activation of Gabra4 by alcohol or high temperature is dependent on the binding of heat shock factor 1 (HSF1) to a short downstream DNA sequence, the alcohol response element (ARE). Alcohol and heat stimulate the translocation of HSF1 from the cytoplasm to the nucleus and the induction of HSF1-dependent genes, Hsp70 and Hsp90, in cultured neurons and in the mouse cerebral cortex in vivo. The reduction of HSF1 levels using small interfering RNA prevented the stimulation of Gabra4 and Hsp70 by alcohol and heat shock. Microarray analysis showed that many ARGs contain ARE-like sequences and that some of these genes are also activated by heat shock. We suggest that alcohol activates phylogenetically conserved pathways that involve intermediates in the heat shock cascade and that sequence elements similar to the ARE may mediate some of the changes in gene expression triggered by alcohol intake, which could be important in a variety of pathophysiological responses to alcohol.

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Section: Discussionmentioning

confidence: 99%

Alcohol Regulates Gene Expression in Neurons via Activation of Heat Shock Factor 1

Pignataro

Miller²,

Ma³

et al. 2007

J. Neurosci.

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confidence: 94%

“…Furthermore, ethanol inhibits L1-mediated neurite outgrowth in CGNs with similar potency to its inhibition of L1 adhesion (11, 12). Finally, drugs that block ethanol inhibition of L1 adhesion also prevent ethanol teratogenesis in mouse embryos (13)(14)(15)(16)(17)(18).L1 is an immunoglobulin transmembrane glycoprotein (8). The extracellular domain (ECD) includes six Ig domains and five fibronectin III repeats.…”

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confidence: 99%

Two Alcohol Binding Residues Interact across a Domain Interface of the L1 Neural Cell Adhesion Molecule and Regulate Cell Adhesion

Dou

Menkari

Shanmugasundararaj

et al. 2011

Journal of Biological Chemistry

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-L1) and mutated L1, we found that cysteine substitution of both residues (E33C/Y418C-L1) significantly increased L1 adhesion above levels observed for WT-L1 or the single cysteine substitutions E33C-L1 or Y418C-L1. The reducing agent ␤-mercaptoethanol (␤ME) reversibly decreased the adhesion of E33C/ Y418C-L1, but had no effect on WT-L1, E33C-L1, or Y418C-L1. Thus, disulfide bond formation occurs between Cys-33 and Cys-418, confirming both the close proximity of these residues and the importance of Ig1-Ig4 interactions in L1 adhesion. Maximal ethanol inhibition of cell adhesion was significantly lower in cells expressing E33C/Y418C-L1 than in those expressing WT-L1, E33C-L1, or Y418C-L1. Moreover, the effects of ␤ME and ethanol on E33C/Y418C-L1 adhesion were non-additive. The cutoff for alcohol inhibition of WT-L1 adhesion was between 1-butanol and 1-pentanol. Increasing the size of the alcohol binding pocket by mutating Glu-33 to Ala-33, increased the alcohol cutoff from 1-butanol to 1-decanol. These findings support the hypothesis that alcohol binding within a pocket bordered by Glu-33 and Tyr-418 inhibits L1 adhesion by disrupting the Ig1-Ig4 interaction.Alcohol exposure during pregnancy is the leading cause of preventable mental retardation in the Western world (1, 2).Depending on timing, dose, and duration of exposure, alcohol causes a range of facial and brain dysmorphology, growth retardation, and cognitive, neurological, and behavioral abnormalities, referred to as fetal alcohol spectrum disorders (FASD) 2 (3). Alcohol is a weak, pleiotropic drug that disrupts fetal development through a variety of mechanisms (4, 5). One potentially important target molecule for alcohol is the L1 neural cell adhesion molecule (CAM), a developmentally critical protein (6 -8).Children with mutations in the gene for L1 have brain lesions that resemble those of children with FASD, including hydrocephalus, agenesis, or hypoplasia of the corpus callosum, and cerebellar dysplasia (7, 9, 10). Concentrations of ethanol attained after one drink inhibit the adhesion of L1 expressed in fibroblasts, neural cell lines, and cerebellar granule neurons (CGN) (6, 7). Furthermore, ethanol inhibits L1-mediated neurite outgrowth in CGNs with similar potency to its inhibition of L1 adhesion (11, 12). Finally, drugs that block ethanol inhibition of L1 adhesion also prevent ethanol teratogenesis in mouse embryos (13)(14)(15)(16)(17)(18).L1 is an immunoglobulin transmembrane glycoprotein (8). The extracellular domain (ECD) includes six Ig domains and five fibronectin III repeats. The first four Ig domains (L1 Ig1-4 ) comprise the minimal elements required for L1 adhesion (19,20). The crystal structure of neurofascin, a member of the L1 family of CAMs, and homology modeling with related CAMs suggest that L1 Ig1-4 folds into a horseshoe structure, with Ig1 in apposition to Ig4 and Ig2 in apposition to (Fig. 6A). Electron microscopy has captured both a horseshoe and an extended conformation of L1 , and functional studies suggest that the hors...

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“…We noted that brain lesions in children with FASD resemble those of children with mutations in the gene for L1 and demonstrated that concentrations of ethanol attained after just one or two drinks inhibit L1 adhesion in cerebellar granule neurons, neural cell lines, and NIH/3T3 fibroblasts (17-19). Importantly, drugs that block ethanol inhibition of L1 adhesion also prevent ethanol teratogenesis in mice (20)(21)(22)(23)(24)(25).…”

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confidence: 99%

Mitogen-activated protein kinase modulates ethanol inhibition of cell adhesion mediated by the L1 neural cell adhesion molecule

Dou

Wilkemeyer

Menkari

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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There is a genetic contribution to fetal alcohol spectrum disorders (FASD), but the identification of candidate genes has been elusive. Ethanol may cause FASD in part by decreasing the adhesion of the developmentally critical L1 cell adhesion molecule through interactions with an alcohol binding pocket on the extracellular domain. Pharmacologic inhibition or genetic knockdown of ERK2 did not alter L1 adhesion, but markedly decreased ethanol inhibition of L1 adhesion in NIH/3T3 cells and NG108-15 cells. Likewise, leucine replacement of S1248, an ERK2 substrate on the L1 cytoplasmic domain, did not decrease L1 adhesion, but abolished ethanol inhibition of L1 adhesion. Stable transfection of NIH/3T3 cells with human L1 resulted in clonal cell lines in which L1 adhesion was consistently sensitive or insensitive to ethanol for more than a decade. ERK2 activity and S1248 phosphorylation were greater in ethanol-sensitive NIH/3T3 clonal cell lines than in their ethanol-insensitive counterparts. Ethanol-insensitive cells became ethanol sensitive after increasing ERK2 activity by transfection with a constitutively active MAP kinase kinase 1. Finally, embryos from two substrains of C57BL mice that differ in susceptibility to ethanol teratogenesis showed corresponding differences in MAPK activity. Our data suggest that ERK2 phosphorylation of S1248 modulates ethanol inhibition of L1 adhesion by inside-out signaling and that differential regulation of ERK2 signaling might contribute to genetic susceptibility to FASD. Moreover, identification of a specific locus that regulates ethanol sensitivity, but not L1 function, might facilitate the rational design of drugs that block ethanol neurotoxicity. P renatal alcohol exposure causes fetal alcohol spectrum disorders (FASD) in up to 2-5% of school-age children and is the leading preventable cause of mental retardation in the Western world (1, 2). The prevalence and presentation of FASD are influenced by the quantity, frequency, and timing of drinking and are modified by a variety of environmental, nutritional, epigenetic, and genetic factors (3-7). The observation that there is greater concordance for fetal alcohol syndrome (FAS) in monozygotic twins than in dizygotic twins suggests that there are susceptibility genes for FASD (8); however, their identification remains elusive. The identification of molecular pathways that regulate sensitivity to ethanol teratogenesis would be helpful in the search for FASD susceptibility genes.One potentially important target of ethanol in the pathogenesis of FASD is the developmentally critical immunoglobulin neural cell adhesion molecule, L1. The homophilic binding of L1 molecules on adjacent cells mediates neuronal migration, axon guidance, and axon fasciculation (9)-developmental events that are disrupted in FASD (10-12). Mutations in the human L1 gene cause brain lesions and neurological abnormalities. Some of these mutations also disrupt L1 homophilic binding (13-16). We noted that brain lesions in children with FASD resemble those of child...

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Peptide-Mediated Protection from Ethanol-Induced Neural Tube Defects

Cited by 57 publications

References 84 publications

Alcohol Regulates Gene Expression in Neurons via Activation of Heat Shock Factor 1

Alcohol Regulates Gene Expression in Neurons via Activation of Heat Shock Factor 1

Two Alcohol Binding Residues Interact across a Domain Interface of the L1 Neural Cell Adhesion Molecule and Regulate Cell Adhesion

Mitogen-activated protein kinase modulates ethanol inhibition of cell adhesion mediated by the L1 neural cell adhesion molecule

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