Enhanced FGFR3 activity in postmitotic principal neurons during brain development results in cortical dysplasia and axonal tract abnormality
| Autor: | Jui-Yen Huang, Hui-Chen Lu, Jason Michael Graf, May Lin Russell, Bruna Baumgarten Krebs, Marisha Lynn Miskus, Eamonn Patrick Duffy |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Genetically modified mouse
Male Excitatory Amino Acids Neurogenesis lcsh:Medicine Glutamic Acid Mitosis Mice Transgenic Biology Fibroblast growth factor Article Glutamatergic Mice Developmental biology medicine Animals Receptor Fibroblast Growth Factor Type 3 lcsh:Science Neurons Multidisciplinary lcsh:R Brain Cell Differentiation Cortical dysplasia medicine.disease Embryonic stem cell Receptors Fibroblast Growth Factor Axons Cortex (botany) Fibroblast Growth Factors Malformations of Cortical Development nervous system Fibroblast growth factor receptor Gain of Function Mutation lcsh:Q Female Neuroscience Signal Transduction |
| Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-20 (2020) |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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