Fetal Alcohol Spectrum Disorders (FASD) is an umbrella term used to describe a myriad of defects associated with prenatal alcohol exposure, including damage to the central nervous system. Alcohol is the most common teratogen, and is recognized as the leading preventable cause of birth defects and developmental disabilities. FASDs are estimated to affect as high as 2 to 5% of children in the United States. While fetal alcohol exposure is widely known to cause FASDs, we understand very little about gene-ethanol interactions and how these interactions elicit abnormal cell behaviors. The behaviors of cells contribute to brain morphogenesis and function. A fundamental cell behavior in the developing brain is neuronal migration. Motor neurons in the vertebrate hindbrain migrate dynamically. These dynamic behaviors are orchestrated by complex genetic hierarchies. Members of the Wnt/planar cell polarity (PCP) signaling pathway, such as vangl2, are highly involved in determining these migratory behaviors. Facial branchiomotor neurons (FBMNs) are a subset of hindbrain neurons that migrate extensively via tangential and radial migratory mechanisms. My preliminary data demonstrate that ethanol interacts with vangl2 during tangential and radial FBMN migration. FBMN migration fails to occur in both control and ethanol-exposed vangl2 mutants. While control vangl2 heterozygotes develop normally, ethanol induces a variety of FBMN defects. Strikingly, many ethanol-exposed vangl2 heterozygotes completely phenocopy the mutant. I hypothesize that combined genetic and ethanol- mediated attenuation of planar cell polarity results in the mispositioning of cranial motor neurons.
In Specific Aim 1 of this proposal, I will use live time-lapsed confocal analyses to assess the tangential and radial migratory behaviors of FBMNs using a transgene to label hindbrain motor neurons.
In Specific Aim 2, I will characterize vangl2-ethanol interactions underlying neuronal migration defects. I will use in situ marker analyses to analyze hindbrain patterning and readouts of planar cell polarity to determine the interaction of ethanol with the Wnt/PCP pathway.
In Specific Aim 3, I will map and functionally characterize ethanol-sensitive mutants that are identified through our ongoing forwards genetic screen. This proposal will provide insight to mechanisms of gene-ethanol interactions that lead to the variety of neural defects associated with FASD. In addition, the data generated from this proposal will be directly applicable to humans due to the high conservation of gene function across vertebrates. This will allow for better identification of individuals at most risk and help with the development of FASD therapeutic treatments.
The purpose of this proposal is to elucidate gene-ethanol interactions underlying the variation of defects observed in patients with Fetal Alcohol Spectrum Disorders (FASD). The results we obtain from this proposal will greatly increase our understanding of the genetics and mechanisms that contribute to FASD etiology.
