Mutations associated with human neural tube defects display disrupted planar cell polarity in Drosophila

Abstract
Data availability
Article and author information
Metrics

Abstract

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.

Data availability

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

Author details

Ashley C Humphries

Cell, Developmental, and Regenerative Biology, Icahn Medical School - Mount Sinai Hospital, New York, United States

Competing interests
The authors declare that no competing interests exist.
Sonali Narang

Pathology, NYU School of Medicine, New York, United States

Competing interests
The authors declare that no competing interests exist.
Marek Mlodzik

Cell, Developmental, and Regenerative Biology, Icahn Medical School - Mount Sinai Hospital, New York, United States

For correspondence
marek.mlodzik@mssm.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0628-3465

Funding

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.

Copyright

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.