RESUMO
Neonatal malnutrition is one of the most common causes of neurological disorders. However, the mechanism of action of the factors associated with neonatal nutrition in the brain remains unclear. In this study, we focused on fibroblast growth factor (FGF) 21 to elucidate the effects of malnutrition on the neonatal brain. FGF21 is an endocrine factor produced by the liver during lactation which is the main source of nutrition during the neonatal period. In this study, malnourishment during nursing mice induced decreased levels of Fgf21 mRNA in the liver and decreased levels of FGF21 in the serum. RNA-seq analysis of neonatal mouse brain tissue revealed that FGF21 controlled the expression of Kalrn-201 in the neonatal mouse brain. Kalrn-201 is a transcript of Kalirin, a Ras homologous guanine nucleotide exchange factor at the synapse. In mouse neurons, FGF21 induced the expression of Kalirin-7 (a Kalirin isoform) by down-regulating Kalrn-201. FGF21-induced Kalirin-7 stimulated neurite outgrowth in Neuro-2a cells. FGF21 also induced Growth hormone-releasing hormone (GHRH) expression in Neuro-2a cells. Kalirin-7 and GHRH expression induced by FGF21 was altered by inhibiting the activity of SH2-containing tyrosine phosphatase (SHP2) which is located downstream of the FGF receptor (FGFR). Additionally, malnourished nursing induced intron retention of the SHP2 gene (Ptpn11), resulting in the alteration of Kalirin-7 and GHRH expression by FGF21 signaling. Ptpn11 intron retention is suggested to be involved in regulating SHP2 activity. Taken together, these results suggest that FGF21 plays a critical role in the induction of neuronal neurite outgrowth and GHRH secretion in the neonatal brain, and this mechanism is regulated by SHP2. Thus, Ptpn11 intron retention induced by malnourished nursing may be involved in SHP2 activity.
