文章基本信息

标题：Enhanced FGFR3 activity in postmitotic principal neurons during brain development results in cortical dysplasia and axonal tract abnormality
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作者：Jui-Yen Huang ; Bruna Baumgarten Krebs ; Marisha Lynn Miskus 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2020
卷号：10
期号：1
页码：1-20
DOI：10.1038/s41598-020-75537-0
出版社：Springer Nature
摘要：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.
其他摘要：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 (FGFR3 K650E ) 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.