N-cadherin-regulated FGFR ubiquitination and degradation control mammalian neocortical projection neuron migration

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...

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Bibliographic Details
Published in:eLife 2019-10, Vol.8
Main Authors: Kon, Elif, Calvo-Jiménez, Elisa, Cossard, Alexia, Na, Youn, Cooper, Jonathan A, Jossin, Yves
Format: Article
Language:English
Subjects:
Animals
Autism
Bipolar cells
Brain
Cadherins
Cadherins - metabolism
Cancer
Cell adhesion & migration
Cell Adhesion Molecules, Neuronal - metabolism
Cerebral cortex
Cloning
Defects
development
Developmental Biology
embryogenesis
Extracellular Matrix Proteins - metabolism
FGFR
Fibroblast growth factor receptors
Heparan sulfate
Lysosomes
MAP Kinase Signaling System
Metastasis
Mice
N-Cadherin
Neocortex
Neocortex - embryology
Nerve Tissue Proteins - metabolism
Neural circuitry
Neurogenesis
neuronal migration
Neurons
Neurons - metabolism
Novels
Phosphorylation
Physiological aspects
Plasmids
Receptors, Fibroblast Growth Factor - metabolism
Reelin protein
Schizophrenia
Serine Endopeptidases - metabolism
Statistical analysis
Ubiquitin
Ubiquitin-proteasome system
Ubiquitination
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Summary: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. Moreover, Reelin, a secreted protein regulating neuronal positioning, prevents FGFR degradation through N-Cadherin, causing 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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.47673