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Proc Natl Acad Sci U S A. 2018 Oct 16;115(42):E9812-E9821. doi: 10.1073/pnas.1812016115. Epub 2018 Oct 3.

Left/right asymmetric collective migration of parapineal cells is mediated by focal FGF signaling activity in leading cells.

Author information

1
Centre de Biologie Intégrative (FR 3743), Centre de Biologie du Développement (UMR5547), Université de Toulouse, CNRS, F-31062 Toulouse, France; myriam.roussigne@univ-tlse3.fr.
2
Centre de Biologie Intégrative (FR 3743), Centre de Biologie du Développement (UMR5547), Université de Toulouse, CNRS, F-31062 Toulouse, France.
3
Centre for Organismal Studies, Heidelberg University, 69120 Heidelberg, Germany.
4
Institut Curie/CNRS/U1021 INSERM, Université Paris Sud (UMR3347), 91405 Orsay, France.
5
Department of Cell and Developmental Biology, University College London, WC1E 6BT London, United Kingdom.
6
Department of Cell and Molecular Biology, Heidelberg University, D-68167 Mannheim, Germany.
7
Center for Integrative Biology, University of Trento, 38123 Trento, Italy.

Abstract

The ability of cells to collectively interpret surrounding environmental signals underpins their capacity to coordinate their migration in various contexts, including embryonic development and cancer metastasis. One tractable model for studying collective migration is the parapineal, a left-sided group of neurons that arises from bilaterally positioned precursors that undergo a collective migration to the left side of the brain. In zebrafish, the migration of these cells requires Fgf8 and, in this study, we resolve how FGF signaling correlates with-and impacts the migratory dynamics of-the parapineal cell collective. The temporal and spatial dynamics of an FGF reporter transgene reveal that FGF signaling is activated in only few parapineal cells usually located at the leading edge of the parapineal during its migration. Overexpressing a constitutively active Fgf receptor compromises parapineal migration in wild-type embryos, while it partially restores both parapineal migration and mosaic expression of the FGF reporter transgene in fgf8 -/- mutant embryos. Focal activation of FGF signaling in few parapineal cells is sufficient to promote the migration of the whole parapineal collective. Finally, we show that asymmetric Nodal signaling contributes to the restriction and leftwards bias of FGF pathway activation. Our data indicate that the first overt morphological asymmetry in the zebrafish brain is promoted by FGF pathway activation in cells that lead the collective migration of the parapineal to the left. This study shows that cell-state differences in FGF signaling in front versus rear cells is required to promote migration in a model of FGF-dependent collective migration.

KEYWORDS:

FGF signaling pathway; Nodal signaling pathway; collective cell migration; left/right brain asymmetry; zebrafish brain development

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