Sertoli Cell-Spermatogenic Cell Interaction: The Insulin-like Growth Factor-II/Cation-Independent Mannose 6-Phosphate Receptor Mediates Changes in Spermatogenic Cell Gene Expression in Mice

Abstract

The insulin-like growth factor (IGF)-II/cation-independent mannose 6-phosphate receptor (CI-MPR) is a multifunctional receptor with distinct binding sites for IGF-II and mannose 6-phosphate (M6P)-bearing glycoproteins. We used the immediate-early response gene c-fos to assay early changes in gene expression in spermatogenic cells in response to ligands for this receptor that are present in the seminiferous epithelium. We confirmed that c-fos behaves as an immediate-early response gene in spermatogenic cells after stimulation of protein kinase C with phorbol ester or after intercellular calcium levels are raised with calcium ionophore. After determining that IGF-II mRNA is present in Sertoli cells, we treated spermatogenic cells with this growth factor and found that it increased c-fos mRNA levels in a dose-dependent manner. Similarly, Sertoli cell-conditioned medium (SCM) caused a dose-dependent increase in c-fos levels in spermatogenic cells isolated from adult mice. This effect was inhibited in the presence of 5 mM M6P, demonstrating that this change in c-fos gene expression was mediated by the IGF-II/Cl-MPR. In addition, SCM treatment of purified pachytene spermatocytes and round spermatids caused a dose-dependent increase in 18S rRNA levels that was completely abolished in the presence of M6P. Our results provide direct evidence that IGF-II/Cl-MPR ligands secreted by Sertoli cells can modulate gene expression in spermatogenic cells and strongly suggest that they are important in the regulation of spermatogenesis.