FGF-FGFR Mediates the Activity-Dependent Dendritogenesis of Layer IV Neurons during Barrel Formation

Abstract

Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) are known for their potent effects on cell proliferation/differentiation and cortical patterning in the developing brain. However, little is known regarding the roles of FGFs/FGFRs in cortical circuit formation. Here we show that //3 and /// mRNAs are expressed in the developing primary somatosensory (S1) barrel cortex. Barrel cortex layer IV spiny stellate cells (bSCs) are the primary recipients of ascending sensory information via thalamocortical axons (TCAs). Detail quantification revealed distinctive phases for bSC dendritogenesis: orienting dendrites toward TCAs, adding dendritic segments, and elongating dendritic length, while maintaining dendritic patterns. Deleting// in bSCs had minimal impact on dendritic polarity but transiently increased the number of dendritic segments. However, 6 d later, FGFR1/2/3 loss of function reduced dendritic branch numbers. These data suggest that FGFs/FGFRs have a role in stabilizing dendritic patterning. Depolarization of cultured mouse cortical neurons upregulated the levels of several / mRNAs within 2 h. , within 6 h of systemic kainic acid administration at postnatal day 6, mRNA levels of, ,, and in S1 cortices were enhanced, and this was accompanied by exuberant dendritogenesis of bSCs by 24 h. Deleting// abolished kainic acid-induced bSC dendritic overgrowth. Finally, FGF9/10 gain of function also resulted in extensive dendritogenesis. Together, our data suggest that FGFs/FGFRs can be regulated by glutamate transmission to modulate/stabilize bSC dendritic complexity. Both male and female mice were used for our study. Glutamatergic transmission plays critical roles in cortical circuit formation. Its dysregulation has been proposed as a core factor in the etiology of many neurological diseases. We found that excessive glutamate transmission upregulated mRNA expression of and their ligands Deleting // not only impaired bSC dendritogenesis but also abolished glutamate transmission-induced dendritic overgrowth. Overexpressing FGF9 or FGF10 in cortical glutamatergic neurons results in excessive dendritic outgrowth within 24 h, resembling the changes induced by excessive glutamate transmission. Our findings provide strong evidence for the physiological role of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) in establishing and maintaining cortical circuits. Perturbing the expression levels of FGFs/FGFRs by excessive glutamatergic neurotransmission could lead to abnormal neuronal circuits, which may contribute to neurological and psychiatric disease.

Fibroblast Growth Factor 22 Inhibits ER Stress-Induced Apoptosis and Improves Recovery of Spinal Cord Injury

“…Previous studies also showed that genetic destruction of the FGF22 signal not only reduces the number of new axons formed in the injured loci but also changes the molecular organization of the forming axons (Terauchi et al, 2010). Therefore, treatment of injured spinal cord with FGF22 can effectively promote axonal regeneration and functional recovery (Huang et al, 2017). The experimental results showed that apoptosis signaling molecules in the FGF22 treatment group were inhibited, which indicated that FGF22 can effectively inhibit endoplasmic reticulum stress, reduce neuronal apoptosis and play a crucial role in neuronal protection.…”

Fibroblast growth factor 9 stimulates neurite outgrowth through NF-kB signaling in striatal cell Huntington’s disease models

“…For example, FGF1 was reported to stimulate neurite outgrowth in PC12 cells through activating FGF receptor 1 (FGFR1) and FGF receptor 3 (FGFR3), with the latter having more potency [33]. Gain of functions for FGF9 and FGF10 has been shown in extensive dendritogenesis in the developing primary somatosensory (S1) barrel cortex [10].…”

“…Fibroblast growth factors (FGFs) influence neuronal morphology [8][9][10] and are involved in the pathogenesis of many neurodegenerative diseases [11][12][13]. Fibroblast growth factor 9 (FGF9), a specific type of FGF, has been reported to regulate neuronal development in vivo [10] and also has been suggested to provide neuroprotective functions in Parkinson's disease (PD) and Huntington's disease (HD), two important neurodegenerative diseases [13][14][15][16]. This suggests that FGF9 may be an exogenous candidate to intervene in these diseases through regulating neuronal morphology.…”

FGF Family: From Drug Development to Clinical Application

“…However, X-ray structural analysis of the FGF ligand-binding region reveals that D3 is folded into a stable immunoglobulin-like structure [ 28 ]. The FGF-FGFR complexes regulate cell proliferation, differentiation, and migration through complicated signal transduction pathways in various tissues [ 29 , 30 , 31 , 32 ]. The relationships of FGF receptors and FGF ligands are shown in Figure 3 .…”