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.
The goal of this proposal is to identify the pathways regulated by a novel ubiquitin ligase critical for the development of the neural tube and placenta. Neural tube and placental defects result in severe complications during pregnancy including spina bifida, miscarriage, long-term disability, preeclampsia and intrauterine growth restriction. The understanding gained from the experiments proposed here may lead to strategies to minimize these complications of pregnancy.
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|Sarkar, Anjali A; Nuwayhid, Samer J; Maynard, Thomas et al. (2014) Hectd1 is required for development of the junctional zone of the placenta. Dev Biol 392:368-80|
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|Tran, Hoanh; Bustos, Daisy; Yeh, Ronald et al. (2013) HectD1 E3 ligase modifies adenomatous polyposis coli (APC) with polyubiquitin to promote the APC-axin interaction. J Biol Chem 288:3753-67|
|Sarkar, Anjali A; Zohn, Irene E (2013) An explant assay for assessing cellular behavior of the cranial mesenchyme. J Vis Exp :|
|Zohn, Irene E (2012) Mouse as a model for multifactorial inheritance of neural tube defects. Birth Defects Res C Embryo Today 96:193-205|
|Zohn, Irene E; Sarkar, Anjali A (2012) Does the cranial mesenchyme contribute to neural fold elevation during neurulation? Birth Defects Res A Clin Mol Teratol 94:841-8|
|Sarkar, Anjali A; Zohn, Irene E (2012) Hectd1 regulates intracellular localization and secretion of Hsp90 to control cellular behavior of the cranial mesenchyme. J Cell Biol 196:789-800|
|Becker-Heck, Anita; Zohn, Irene E; Okabe, Noriko et al. (2011) The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation. Nat Genet 43:79-84|
|Zohn, Irene E; Sarkar, Anjali A (2010) The visceral yolk sac endoderm provides for absorption of nutrients to the embryo during neurulation. Birth Defects Res A Clin Mol Teratol 88:593-600|
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