title: Par3 controls neural crest migration by promoting microtubule catastrophe during contact inhibition of locomotion.
abstract: There is growing evidence that contact inhibition of locomotion (CIL) is essential for morphogenesis and its failure is thought to be responsible for cancer invasion; however, the molecular bases of this phenomenon are poorly understood. Here we investigate the role of the polarity protein Par3 in CIL during migration of the neural crest, a highly migratory mesenchymal cell type. In epithelial cells, Par3 is localised to the cell-cell adhesion complex and is important in the definition of apicobasal polarity, but the localisation and function of Par3 in mesenchymal cells are not well characterised. We show in Xenopus and zebrafish that Par3 is localised to the cell-cell contact in neural crest cells and is essential for CIL. We demonstrate that the dynamics of microtubules are different in different parts of the cell, with an increase in microtubule catastrophe at the collision site during CIL. Par3 loss-of-function affects neural crest migration by reducing microtubule catastrophe at the site of cell-cell contact and abrogating CIL. Furthermore, Par3 promotes microtubule catastrophe by inhibiting the Rac-GEF Trio, as double inhibition of Par3 and Trio restores microtubule catastrophe at the cell contact and rescues CIL and neural crest migration. Our results demonstrate a novel role of Par3 during neural crest migration, which is likely to be conserved in other processes that involve CIL such as cancer invasion or cell dispersion.
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Moore
authors.forename: Eric
authors.initials: E
authors.lastname: Theveneau
authors.forename: Sara
authors.initials: S
authors.lastname: Pozzi
authors.forename: Paula
authors.initials: P
authors.lastname: Alexandre
authors.forename: Joanna
authors.initials: J
authors.lastname: Richardson
authors.forename: Anne
authors.initials: A
authors.lastname: Merks
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
authors.forename: Jubin
authors.initials: J
authors.lastname: Kashef
authors.forename: Claudia
authors.initials: C
authors.lastname: Linker
authors.forename: Roberto
authors.initials: R
authors.lastname: Mayor
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D003260:Contact Inhibition; D008870:Microtubules / Q000378:metabolism*; D009024:Morphogenesis; D009432:Neural Crest / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D029867:Xenopus Proteins / Q000235:genetics / Q000502:physiology*; D014982:Xenopus laevis / Q000378:metabolism / Q000502:physiology*; D015027:Zebrafish / Q000378:metabolism / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; C586203:Pard3 protein, Xenopus; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; C486818:pard3ab protein, zebrafish
keywords: Cell migration; Cell polarity; Contact inhibition of locomotion; Microtubule catastrophe; Neural crest; Par3; Pard3; Rac; Trio