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

Abstract

31Planar cell polarity (PCP) and neural tube defects (NTDs) are linked, with a subset of NTD 32 patients found to harbour mutations in PCP genes, but there is limited data on whether these 33 mutations disrupt PCP signaling in vivo. The core PCP gene Van Gogh (Vang), Vangl1/2 in 34 mammals, is the most specific for PCP. We thus addressed potential causality of NTD-35 associated Vangl1/2 mutations, from either mouse or human patients, in Drosophila allowing 36 intricate analysis of the PCP pathway. Introducing the respective mammalian mutations into 37 Drosophila Vang revealed defective phenotypic and functional behaviors, with changes to 38 Vang localization, post-translational modification, and mechanistic function, such as its 39 ability to interact with PCP effectors. Our findings provide mechanistic insight into how 40 different mammalian mutations contribute to developmental disorders and strengthen the 41 link between PCP and NTD. Importantly, analyses of the human mutations revealed that 42 each is a causative factor for the associated NTD.43 108 Wnt/Frizzled-PCP pathway. Besides the four-pass trans-membrane protein Vang (Vangl1 109 and Vangl2 in mammals, see above), which was -like all other core PCP factors -originally 110 discovered in Drosophila (Taylor et al., 1998), a.k.a. strabismus/stbm (Wolff and Rubin, 111 1998), they include the atypical cadherin Flamingo (Fmi; Celsr in mammals), the seven-pass 112 transmembrane protein Frizzled (Fz; Fzd in vertebrates with several family members), and 113 the cytoplasmic proteins Dishevelled (Dsh; Dvl in mammals), Diego (Dgo; Inversin/Diversin 114 in vertebrates), and Prickle (Pk). The pathway is synonymous with the asymmetric

Structural basis of the human Scribble–Vangl2 association in health and disease

“…Similarly to Scribble, Vangl2 is essential in early embryonic development where its loss leads to neural tube defects as well as disruption in the cochleae inner ear hair bundle orientation [ 10 , 16 ]. A number of mutations in human Vangl2 have also been shown to be associated to neural tube closure defects [ 17 ] with recent studies implicating disruption of planar cell polarity as the causative factor for these mutations [ 18 ]. Importantly, Vangl2 genetically interacts with Scribble to regulate planar cell polarity processes in the mouse [ 10 , 11 , 19 , 20 ].…”

Cell non-autonomy amplifies disruption of neurulation by mosaic Vangl2 deletion

“…Human mutations in core PCP genes disrupt this pathway when engineered into Drosophila 66 . Mammalian embryonic tissues achieve planar polarity through ligand gradient-sensing, as in the case of Fat/Dachsous PCP, or through non-autonomous propagation of directionality through asymmetrical complex organisation characteristic of the 'core' PCP pathway studied here 17,67 .…”

From Neural Crest to Definitive Roof Plate: The Dynamic Behavior of the Dorsal Neural Tube

“…The development of the dorsal NT embodies basic processes in development: the regulation of cell proliferation, cellular movements and cell elongation, epithelial-mesenchymal transitions, lineage decisions, and relationships between them. Aberrant signaling during critical phases leads to disease, ranging from defects in NT closure [ 142 , 143 , 144 ], lack of dorsal cell types [ 50 , 92 , 133 ], neurocristopathies [ 145 , 146 ], and tumors generated from RP derivatives such as choroid plexus papillomas or carcinomas [ 147 ]. Our expanding knowledge of basic mechanisms of development should assist us in developing animal models for addressing their etiology, prevention and treatment.…”