Novel Ubiquitin Dependent Pathways Regulating Neural Tube Closure & Placentation

描述（由申请人提供）：神经管和胎盘缺陷会导致怀孕期间出现严重并发症。神经管缺陷包括脊柱裂和无脑畸形是影响人类的一些最常见的形态学出生缺陷，导致胎儿死亡或长期残疾。胎盘发育缺陷可导致流产、先兆子痫或宫内生长受限。对小鼠的研究表明，神经管和胎盘的发育都需要大量基因的活动，我们才刚刚开始了解这些基因如何组织成控制发育的途径。此外，这些途径的活性如何被微调以更严格地控制蛋白质作用的强度和持续时间仍然是未知的。泛素化是一种翻译后修饰，在调节蛋白质活性中起重要作用。泛素化的重要性由许多由泛素化途径破坏引起的人类疾病（包括安吉曼综合征和帕金森病）说明。尽管泛素化的重要性已被公认，但它在胚胎发育过程中控制蛋白质活性的作用才刚刚开始被认识。我们发现了一种新的泛素连接酶，它在神经管闭合和胎盘形成中起着关键作用。我们的目标是了解这种新型泛素连接酶如何调节蛋白质功能，调节神经管和胎盘的发育。这里提出的实验将在这个小鼠突变体的胎盘表型的特点，提供有价值的洞察调节的途径。此外，我们将使用生物化学，细胞生物学和遗传学的方法，以确定底物的泛素连接酶介导的神经管和胎盘缺陷，在我们的突变小鼠品系。这些实验将确定这种新型泛素连接酶调控神经管和胎盘发育的途径。

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.