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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD058629-04
Application #
8446209
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Henken, Deborah B
Project Start
2010-04-15
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$325,151
Indirect Cost
$136,110
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
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