RT Journal Article
SR Electronic
T1 Enhanced FGFR3 activity in post-mitotic principal neurons during brain development results in cortical dysplasia and axon miswiring
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.02.073924
DO 10.1101/2020.05.02.073924
A1 Jui-Yen Huang
A1 Bruna Baumgarten Krebs
A1 Marisha Lynn Miskus
A1 May Lin Russell
A1 Eamonn Patrick Duffy
A1 Jason Michael Graf
A1 Hui-Chen Lu
YR 2020
UL http://biorxiv.org/content/early/2020/05/03/2020.05.02.073924.abstract
AB Abnormal levels of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) have been detected in various neurological disorders. The potent impact of FGF-FGFR in multiple embryonic developmental processes makes it challenging to elucidate their roles in post-mitotic neurons. Taking an alternative approach, we directly examined the impact of aberrant FGFR function after neurogenesis by generating a FGFR gain-of-function (GOF) transgenic mouse which expresses constitutively activated FGFR3 (FGFR3K650E) in post-mitotic glutamatergic neurons. We found that enhanced FGFR activity in glutamatergic neurons results in abnormal radial migration and axonal miswiring. Regarding the lamination phenotype in GOF brains, we found later-born Cux1-positive neurons are dispersed throughout the GOF cortex. Such a cortical migration deficit is likely caused, at least in part, by a significant reduction of the radial processes normally projecting from the radial glia cells (RGCs). In addition, FGFR3 GOF also results in the misrouting of several long-range axonal projections, including the corpus callosum, anterior commissure, and postcommissural fornix. RNA-sequencing analysis of the GOF embryonic cortex reveals significant alterations in several pathways involved in cell cycle regulation and axonal pathfinding. Collectively, our results suggest that FGFR hyperfunction in post-mitotic neurons at the late embryonic stage result in cortical dysplasia and circuit miswiring.Competing Interest StatementThe authors have declared no competing interest.