Novel Ubiquitin Dependent Pathways Regulating Neural Tube Closure & Placentation

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DESCRIPTION (provided by applicant): Neural tube and placental defects result in severe complications during pregnancy. Neural tube defects including spina bifida and anencephaly are some of the most common morphological birth defects affecting humans resulting in death of the fetus or long-term disability. Defects in development of the placenta can lead to miscarriage, preeclampsia or intrauterine growth restriction. Studies in mouse have demonstrated that both neural tube and placental development require the activity of a large number of genes and we are only beginning to understand how these genes organize into pathways to control development. Additionally, how the activity of these pathways is fine-tuned to more tightly control the strength and duration of protein action remains unknown. Ubiquitination is a posttranslational modification that plays an important role in regulating protein activity. The importance of ubiquitination is illustrated by the numerous human diseases caused by disruption of ubiquitination pathways including Angelmans Syndrome and Parkinson's disease. In spite of the recognized importance of ubiquitination, its role in controlling protein activity during embryonic development is only beginning to become appreciated. We identified a novel ubiquitin ligase that plays a critical role in neural tube closure and placentation. Our goal is to understand how regulation of protein function by this novel ubiquitin ligase regulates development of the neural tube and placenta. Experiments proposed here will characterize the placenta phenotypes in this mouse mutant to provide valuable insight into the pathways regulated. Additionally, we will use biochemical, cell biological and genetic approaches to identify the substrate of the ubiquitin ligase that mediates neural tube and placental defects in our mutant mouse line. These experiments will define the pathways regulated by this novel ubiquitin ligase to control neural tube and placental development.