Alcohol is a potent neurotoxicant, and prenatal alcohol exposure is the leading known cause of mental retardation. One affected population is the neural crest. Our past work found that clinically relevant ethanol exposures (20-80 mM) cause neural crest apoptosis;a hitherto unexplained observation is that the timing of this death coincides with the endogenous apoptosis of these cells. Our current award established that ethanol causes an intracellular Ca2+ transient that is necessary and sufficient to cause neural crest apoptosis. This Ca2+ transient originates from ethanol's stimulation of Gai2/3, and Gpy-mediated activation of PI-PLC. We recently discovered that ethanol and its Ca2+ transient rapidly suppress canonical Wnt/p- catenin signals within neural crest;these provide essential trophic support to neural crest and govern their morphogenesis. Conversely, the G protein/PI-PLC/Ca pathway that is activated in neural crest by ethanol converges on a distinct Wnt pathway, known as the non-canonical Wnt/Ca pathway, that uses G protein and PI-PLC-mediated Ca2+ release to repress canonical Wnt signals and cause the endogenous cell death of neural crest. Studies in this competing renewal test the hypothesis that the ethanol-stimulated Ca2+ transient is apoptotic because it suppresses the Wnt/S-catenin signals that provide trophic support to the neural crest. We further propose that the ethanol-induced Ca2+ transient converges on and activates the noncanonical Wnt/Ca signals that similarly repress 3-catenin to cause endogenous neural crest death.
Aim 1 tests whether the ethanol-induced Ca2+ transient suppresses the Wnt/(3-catenin signals that govern neural crest development and survival. We will investigate whether the loss of trophic support provided by Wnt/p-catenin contributes to their apoptosis.
Aim 2 tests whether ethanol's suppression of Wnt/p-catenin is mediated by calmodulin-dependent kinase II (CaMKII), which converts the Ca2+ transient into a pro-apoptosis cellular signal.
Aim 3 tests whether the ethanol-induced Ca2+ transient in neural crest disrupts Wnt/p-catenin and causes apoptosis because it converges on and activates the Wnt/Ca signals that govern the coincident endogenous cell death of neural crest. These studies are a logical extension of the current award. We continue to use our established chick embryo model, which replicates the alcohol responses of mammals including humans, has well-described neural crest development, and is now accessible for genetic manipulation using electroporetic transfection of gain- of-function or siRNA expression vectors. Wnt activities are highly conserved among vertebrates. They are important regulators of cell growth and differentiation in diverse tissues, raising the possibility that Wnts represent a novel target for alcohol action in the fetus and the adult.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
3R37AA011085-14S1
Application #
8134114
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Hereld, Dale
Project Start
2010-09-05
Project End
2011-08-31
Budget Start
2010-09-05
Budget End
2011-08-31
Support Year
14
Fiscal Year
2010
Total Cost
$74,250
Indirect Cost
Name
University of Wisconsin Madison
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Helfrich, Kaylee K; Saini, Nipun; Kling, Pamela J et al. (2018) Maternal iron nutriture as a critical modulator of fetal alcohol spectrum disorder risk in alcohol-exposed pregnancies. Biochem Cell Biol 96:204-212
Flentke, George R; Smith, Susan M (2018) The avian embryo as a model for fetal alcohol spectrum disorder. Biochem Cell Biol 96:98-106
Huebner, Shane M; Helfrich, Kaylee K; Saini, Nipun et al. (2018) Dietary Iron Fortification Normalizes Fetal Hematology, Hepcidin, and Iron Distribution in a Rat Model of Prenatal Alcohol Exposure. Alcohol Clin Exp Res 42:1022-1033
Berres, Mark E; Garic, Ana; Flentke, George R et al. (2017) Transcriptome Profiling Identifies Ribosome Biogenesis as a Target of Alcohol Teratogenicity and Vulnerability during Early Embryogenesis. PLoS One 12:e0169351
Huebner, Shane M; Blohowiak, Sharon E; Kling, Pamela J et al. (2016) Prenatal Alcohol Exposure Alters Fetal Iron Distribution and Elevates Hepatic Hepcidin in a Rat Model of Fetal Alcohol Spectrum Disorders. J Nutr 146:1180-8
Amos-Kroohs, Robyn M; Fink, Birgit A; Smith, Carol J et al. (2016) Abnormal Eating Behaviors Are Common in Children with Fetal Alcohol Spectrum Disorder. J Pediatr 169:194-200.e1
Huebner, Shane M; Tran, Tuan D; Rufer, Echoleah S et al. (2015) Maternal iron deficiency worsens the associative learning deficits and hippocampal and cerebellar losses in a rat model of fetal alcohol spectrum disorders. Alcohol Clin Exp Res 39:2097-107
Smith, Susan M; Garic, Ana; Flentke, George R et al. (2014) Neural crest development in fetal alcohol syndrome. Birth Defects Res C Embryo Today 102:210-20
Flentke, George R; Klingler, Rebekah H; Tanguay, Robert L et al. (2014) An evolutionarily conserved mechanism of calcium-dependent neurotoxicity in a zebrafish model of fetal alcohol spectrum disorders. Alcohol Clin Exp Res 38:1255-65
Garic, Ana; Berres, Mark E; Smith, Susan M (2014) High-throughput transcriptome sequencing identifies candidate genetic modifiers of vulnerability to fetal alcohol spectrum disorders. Alcohol Clin Exp Res 38:1874-82

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