Abstract
Fibroblast growth factor 9 (FGF9) is a multifunctional polypeptide belonging to the FGF family and has functions related to bone formation, lens-fiber differentiation, nerve development, gap-junction formation and sex determination. In a previous study, we demonstrated that FGF9 stimulates the production of testosterone in mouse Leydig cells. In the present study, we used both primary mouse Leydig cells and MA-10 mouse Leydig tumor cells to further investigate the molecular mechanism of FGF9-stimulated steroidogenesis. Results showed that FGF9 significantly activated steroidogenesis in both mouse primary and tumor Leydig cells (p<0.05). Furthermore, FGF9 significantly induced the expression of phospho-Akt at 0.5 and 24 hr, phospho-JNK at 0.25, 0.5, and 24 hr, phospho-p38 at 0.5 hr, and phospho-ERK1/2 from 0.25 to 24 hr in primary Leydig cells (p<0.05). Also, FGF9 significantly up-regulated the expression of phospho-Akt at 3 hr, phospho-JNK at 0.25 hr, and phospho-ERK1/2 at 1 and 3 hr in MA-10 cells (p<0.05). Using specific inhibitors of Akt, JNK, p38, and ERK1/2, we further demonstrated that the inhibitors of Akt and ERK1/2 significantly suppressed the stimulatory effect of FGF9 on steroidogenesis in mouse Leydig cells. In conclusion, FGF9 specifically activated the Akt and ERK1/2 in normal mouse Leydig cells and the Akt, JNK and ERK1/2 in MA-10 mouse Leydig tumor cells to stimulate steroidogenesis.
Highlights
Fibroblast growth factor 9 (FGF9) was first isolated from the culture supernatant of the human glioma cell line NMC-G1 [1] and has been shown to participate in neuron development, bone formation, lens-fiber differentiation, gap-junction formation, sex determination, and steroidogenesis [2,3,4,5,6,7,8]
We demonstrated that FGF9 increases testosterone production in mouse primary Leydig cells through the Ras/ mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and PKA pathways but not through the PLCc pathway [8]
We further showed that FGF9 could induce testosterone and progesterone production in mouse primary and tumor Leydig cells, respectively, through the induction of phospho-Akt, -jun N-terminal kinase (JNK), -p38, and/or -ERK1/2, which are the downstream components of Ras and MAPK signal transduction pathways
Summary
Fibroblast growth factor 9 (FGF9) was first isolated from the culture supernatant of the human glioma cell line NMC-G1 [1] and has been shown to participate in neuron development, bone formation, lens-fiber differentiation, gap-junction formation, sex determination, and steroidogenesis [2,3,4,5,6,7,8]. Studies have demonstrated that FGF9 is expressed in the embryonic and postnatal male reproductive tract [3]. Other studies have shown that FGF9 participates in sex determination by maintaining SOX9 expression and seminiferous tubule formation, and failure of FGF9 expression results in abnormal testicular development in humans [9,10,11]. Together, these evidences suggest that FGF9 plays an important role in male gonadal development and function. We demonstrated that FGF9 increases testosterone production in postnatal mouse Leydig cells [8], implying that FGF9 may regulate steroidogenesis in male reproductive tissues
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