Abstract
Planar cell polarity (PCP) and neural tube defects (NTDs) are linked, with a subset of NTD patients found to harbor 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.
Highlights
Neural tube closure defects (NTDs) are common congenital malformations in humans, affecting approximately 1 in 1000 births
While mutations have been observed along the entire span of the VANGL1/2 genes in human NTD patients, mutations known to be causative for NTD in the mouse all map to the C-terminal tail (Chen et al, 2013; El-Hassan et al, 2018; Guyot et al, 2011; Kibar et al, 2001; Murdoch et al, 2001)
Our data revealed that the mutations analyzed fall into different functional categories and that all patient derived mutations tested are causative of planar cell polarity (PCP) defects, and likely causative of NTD in the patients
Summary
Neural tube closure defects (NTDs) are common congenital malformations in humans, affecting approximately 1 in 1000 births. A recessive mVangl2Lp mutation was discovered (with substitution R259L) that gave an apparently normal phenotype in heterozygotes In this case, only 47% of homozygote animals displayed a looped tail and 12% developed spina bifida, a milder NTD as compared to craniorachischisis, leading to the suggestion that this Lp mutation is a hypomorphic Vangl LOF allele (Guyot et al, 2011; Wang et al, 2006b; Yin et al, 2012). Our analyses demonstrate in molecular detail the nature of the different VANGL1/2 alleles These alleles display defective PCP signaling in vivo, indicating their causative association with the NTD phenotypes of the human patient mutations
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
