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

Elif Kon,Elisa Calvo-Jiménez,Alexia Cossard,Yves Jossin,Youn Na,Jonathan A Cooper

doi:10.7554/elife.47673

Elif Kon, Elisa Calvo-Jiménez + Show 4 more

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https://doi.org/10.7554/elife.47673

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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. 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.

Highlights

The mammalian neocortex has a complicated structure, with multiple layers of different types of neurons linked together in microcircuits
These results suggest that the FGFR1-3 cytoplasmic domains are important for multipolar migration
The knock-down of FGFR3 resulted in a small, statistically non-significant effect on cell positioning (Figure 1b, Figure 1—figure supplement 1). These results suggest that Fibroblast growth factors (FGFs) receptors (FGFRs) work redundantly with a prominent role for FGFR1 and FGFR2

Summary

Introduction

The mammalian neocortex has a complicated structure, with multiple layers of different types of neurons linked together in microcircuits. In addition to FGFs and heparan sulfate, cell surface proteins including neural cadherin (NCad or CDH2), epidermal cadherin (ECad or CDH1), L1 cell adhesion molecule (L1CAM) and neural CAM (NCAM) can bind to and activate FGFRs (Williams et al, 1994; Williams et al, 2001; Suyama et al, 2002; Brown et al, 2016) Both NCad and FGFRs are highly expressed during the epithelial-mesenchymal transition of cancer cells and their interaction may be important for metastasis. Inhibition of Erk1/2 activity in the developing cerebral cortex induces a similar phenotype as FGFR or Rap inhibition These data reveal a novel function of FGFRs in cortical projection neuron migration and the control of its activity. We identified FGFRs as mediating Reelin activation of Erk1/2 to control migration during the multipolar phase These findings provide insights into FGFR mutation-related inherited brain diseases

Results

Discussion

Materials and methods