One of the most devastating consequences of alcohol misuse is its teratogenic effects on fetal development, particularly in the development of the brain and the formation of its complex circuitry. These permanent developmental deficits caused by alcohol misuse are referred to as Fetal Alcohol Spectrum Disorder (FASD). Recent findings have demonstrated that fetal alcohol exposure results in wide-ranging and adaptive alterations of gene expression within the developing cerebral cortex. Such coordinated gene expression changes are regulated mainly by highly specified transcription factors and miRNAs. In addition, recent studies on budding yeast and fruit fly have demonstrated that RNA binding proteins coordinately regulate the post-transcriptional modification of specific types of mRNAs in response to rapid environmental changes. This post-transcriptional regulatory complex of specific mRNAs and RNA binding proteins, known as RNA-operons, are suggested to have important roles in cellular adaptation to environment and diseases. However, the response of RNA-operons as a result of alcohol exposure within the mammalian brain remains unknown. We have recently found that the RNA binding protein, Rbm39, is upregulated in response to ethanol exposure in both the human and mouse embryonic cortex. Our preliminary data suggests that the upregulation of Rbm39 is required for protecting neural progenitor cells from both cell death and cell cycle arrest in embryonic mouse cortices exposed to ethanol. However, alterations in Rbm39 expression, whether due to loss- or gain-of- function, do not show obvious effects on normal cortical development. These results suggest that the Rbm39 plays specific roles resulting from ethanol exposure. In addition, we have found that the Rbm39 regulates the post-transcriptional modifications of specific mRNAs that are required for adaptive cellular protection from ethanol. Therefore, we hypothesize that the Rbm39 coordinates post-transcriptional modification through RNA- operons after exposure to ethanol, providing an immediate and adaptive system in protecting cells within the embryonic cortex. We will examine this hypothesis through three discrete aims.
Aim 1 will define the requirement of Rbm39 for neural protection by knocking down Rbm39 in embryonic cortices exposed to ethanol.
Aim 2 will determine whether exogenous increased of Rbm39 activity on RNA- operons can further reduce the brain damages by ethanol.
Aim3 will examine whether Rbm39 orchestrates immediate post-transcriptional modification of specific genes in response to ethanol exposure.
This study is, as far as we know, the first attempt to define alcohol-specific post-transcriptional control by introducing the concept of RNA-operons. Results from these studies will provide a novel understanding of the brain-intrinsic defense system, and of why the brains fail to be protected following fetal alcohol exposure despite the existence of such intrinsic system. The study will have a powerful impact on both the FASD and alcohol research communities. This research will also be a critical foundation for providing novel strategies focusing on post-transcriptional modification in preventing or alleviating issues linked to prenatal alcohol exposure.
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