Mutations associated with human neural tube defects display disrupted planar cell polarity in Drosophila
Planar cell polarity (PCP) and neural tube defects (NTDs) are linked, with a subset of NTD patients found to harbour mutations in PCP genes, but there is limited data on whether these mutations disrupt PCP signaling in vivo. The core PCP gene Van Gogh (Vang), Vangl1/2 in mammals, is the most specific for PCP. We thus addressed potential causality of NTD-associated Vangl1/2 mutations, from either mouse or human patients, in Drosophila allowing intricate analysis of the PCP pathway. Introducing the respective mammalian mutations into Drosophila Vang revealed defective phenotypic and functional behaviors, with changes to Vang localization, post-translational modification, and mechanistic function, such as its ability to interact with PCP effectors. Our findings provide mechanistic insight into how different mammalian mutations contribute to developmental disorders and strengthen the link between PCP and NTD. Importantly, analyses of the human mutations revealed that each is a causative factor for the associated NTD.
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2 and 5.
Article and author information
National Institute of General Medical Sciences (R35 GM127103)
- Marek Mlodzik
National Eye Institute (R01 EY013256)
- Marek Mlodzik
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Hugo J Bellen, Baylor College of Medicine, United States
- Received: November 12, 2019
- Accepted: March 31, 2020
- Accepted Manuscript published: April 1, 2020 (version 1)
- Version of Record published: April 23, 2020 (version 2)
© 2020, Humphries et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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