Abstract
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 postmitotic neurons. Taking an alternative approach to examine the impact of aberrant FGFR function on glutamatergic neurons, we generated a FGFR gain-of-function (GOF) transgenic mouse, which expresses constitutively activated FGFR3 (FGFR3K650E) in postmitotic glutamatergic neurons. We found that GOF disrupts mitosis of radial-glia neural progenitors (RGCs), inside-out radial migration of post-mitotic glutamatergic neurons, and axonal tract projections. In particular, late-born CUX1-positive neurons are widely 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 projecting from RGCs. RNA-sequencing analysis of the GOF embryonic cortex reveals significant alterations in several pathways involved in cell cycle regulation and axonal pathfinding. Collectively, our data suggest that FGFR3 GOF in postmitotic neurons not only alters axonal growth of postmitotic neurons but also impairs RGC neurogenesis and radial glia processes.
Highlights
Abnormal levels of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) have been detected in various neurological disorders
To explore the role of FGF-FGFR signaling in cortical neurons after neurogenesis, we expressed a constitutively activated FGFR3 mutant, FGFR3K650E, in postmitotic glutamatergic neurons
Western blotting of cortices prepared from postnatal day 7th (P7) control and GOF mice reveals a significant increase in the abundance of phosphorylated FRS2α (p = 0.0402) and ERK1/2 (p = 0.0015), normalized to total FRS2α and ERK1/2, in GOF cortex compared to their littermate controls, verifying an increase of FGFR3 signaling (Fig. 1B,C)
Summary
Abnormal levels of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) have been detected in various neurological disorders. Late-born CUX1-positive neurons are widely 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 projecting from RGCs. RNA-sequencing analysis of the GOF embryonic cortex reveals significant alterations in several pathways involved in cell cycle regulation and axonal pathfinding. We employed the NEX-Cre line[29] to express FGFR3K650E (a constitutively active FGFR3) mainly in postmitotic glutamatergic neurons to elucidate the role of FGFR3 in neuronal differentiation and neural circuit wiring. Results from this gain-of-function (GOF) approach reveal the potent impacts of FGFR3 hyperfunction on cortical and hippocampal lamination, brain size, neuronal differentiation, and axonal pathfinding. Despite GOF of FGFR3 in postmitotic neurons, the proliferative capacity and radial processes of RGCs are impaired and result in defective cortical lamination
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
