N-cadherin-regulated FGFR ubiquitination and degradation control mammalian neocortical projection neuron migration
- Université Catholique de Louvain, Belgium
- Fred Hutchinson Cancer Research Center, United States
Abstract
The functions of FGF receptors (FGFRs) in early development of the cerebral cortex are well established. Their functions in the migration of neocortical projection neurons, however, are unclear. We have found that FGFRs regulate multipolar neuron orientation and the morphological change into bipolar cells necessary to enter the cortical plate. Mechanistically, our results suggest that FGFRs are activated by N-Cadherin. N-Cadherin cell-autonomously binds FGFRs and inhibits FGFR K27- and K29-linked polyubiquitination and lysosomal degradation. Accordingly, FGFRs accumulate and stimulate prolonged Erk1/2 phosphorylation. Neurons inhibited for Erk1/2 are stalled in the multipolar zone. We found that Reelin, prevents FGFR degradation in an N-Cadherin-dependent manner and stimulates prolonged, FGFR-dependent, Erk1/2 phosphorylation. These findings reveal novel functions for FGFRs in cortical projection neuron migration, suggest a physiological role for FGFR and N-Cadherin interaction in vivo and identify Reelin as an extracellular upstream regulator and Erk1/2 as downstream effectors of FGFRs during neuron migration.
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All data generated or analyzed during this study are included in the manuscript and supporting files
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Funding
Fonds De La Recherche Scientifique - FNRS (J.0129.15)
- Yves Jossin
Fonds De La Recherche Scientifique - FNRS (J.0179.16)
- Yves Jossin
Fonds De La Recherche Scientifique - FNRS (T.0243.18)
- Yves Jossin
Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture
- Elif Kon
- Elisa Calvo-Jimenez
- Alexia Cossard
National Institutes of Health (R01-NS080194)
- Jonathan A Cooper
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: CD1 mice were bred in standard conditions and animal procedures were carried out in accordance with European guidelines and approved by the animal ethics committee of the Université Catholique de Louvain under the protocol number: 2017/UCL/MD/009.
Copyright
© 2019, Kon et al.
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.
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N-cadherin-regulated FGFR ubiquitination and degradation control mammalian neocortical projection neuron migration
eLife 8:e47673.
https://doi.org/10.7554/eLife.47673
