Fibroblast growth factor 21 affects the colocalization of post-synaptic density 95 and Kalirin7 through...

Endocrine Fibroblast Growth Factor21 (FGF21) is mainly produced in the liver and regulates energy metabolism. Although FGF21 is a systemic signaling factor that functions in the central nervous system (CNS), its precise role remains unknown. We have previously reported that FGF21 regulates the expression of genes associated with neurite outgrowth and is involved in the induction of growth hormone-releasing hormone (GHRH) secretion in the hypothalami of neonatal mice. In this study, we aimed to clarify the role of FGF21 in the neonatal mouse hypothalamus by identifying the regulatory mechanism of gene expression by FGF21 and its effect on neuronal function. We observed that FGF21 signaling altered the expression of specific genes and small RNAs in neonatal mouse hypothalamic tissues. An investigation of the function of a set of genes whose expression is regulated through FGF21-induced small RNA in the neonatal mouse hypothalamus revealed that FGF21 downregulates the expression of Mmu-miRNA-7240-5p, resulting in the induction of intron retention of cylindromatosis lysine 63 deubiquitinase (CYLD). This consequently led to suppressed CYLD expression in neurons, which preserved post-synaptic density 95 (PSD95) ubiquitination, promoting the colocalization of PSD95/Kalirin7. In summary, FGF21 maintained PSD95 ubiquitination by suppressing CYLD via Mmu-miRNA-7240-5p, resulting in the colocalization of PSD95 and Kalirin7. As the colocalization of PDS95 and Kalirin7 is important for spine formation, our results suggest that FGF21 promotes neuronal spine formation in the murine hypothalamus.