Enhanced FGFR3 activity in postmitotic principal neurons during brain development results in cortical dysplasia and axonal tract abnormality

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.

Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

“…Of the variants identified in this study, about half are in or near genes expressed in the brain. These include FGFR3 , the gene encoding fibroblast growth factor receptor 3 that influences development of cortical and hippocampal neurons 47 , KCNG2 , encoding a voltage-gated potassium channel expressed in hippocampus and harboring variants influencing educational attainment 48 , depression 49 and response to opiates 50 , and GH1 , expressed in the pituitary and linked to hypersensitivity to pain and chronic pain development 51 . Future studies are needed to address what roles these, and other genes suggested by our findings, have in the development of back pain.…”

DOT1L activity affects cell lineage progression in the developing brain by controlling metabolic programs

“…4B ). Increased levels of Fgfr3 were reported to induce cell cycle exit of progenitors (Huang et al, 2020). Thus, the scRNA-seq data reflect at the transcriptional level our data on single-cell reconstruction of lineage progression, and both experimental attempts show a general increase in the neurogenic potential of APs upon DOT1L inhibition.…”

“…4B). Increased levels of Fgfr3 were reported to induce cell cycle exit of progenitors (Huang et al, 2020).…”

Cerebral cortex maldevelopment in syndromic craniosynostosis

“…Because of different genetic mechanisms among the various syndromes, inborn errors of cortical folding or maturation may exist and may vary significantly among syndrome and subtype. For example, FGFR genes are critical in cortical development processes including neuronal migration and stabilization of dentritic patterning and TWIST1 is involved in cranial mesodermal development 33–35 . Other factors may also influence cortical development including craniocerebral disproportion, intracranial hypertension, surgical intervention, and associated anesthesia burden.…”

“…For example, FGFR genes are critical in cortical development processes including neuronal migration and stabilization of dentritic patterning and TWIST1 is involved in cranial mesodermal development. 33 , 34 , 35 Other factors may also influence cortical development including craniocerebral disproportion, intracranial hypertension, surgical intervention, and associated anesthesia burden. Future studies with consistent serial imaging and detailed neuropsychological assessment may provide greater insight regarding specific causes of the cortical maldevelopment described here.…”