REGULATION OF SERTOLI-CELL DIFFERENTIATION BY THE TESTICULAR PARACRINE FACTOR PMODS - POTENTIAL ROLE OF IMMEDIATE-EARLY GENES

Testicular peritubular cells produce a paracrine factor, PModS, under androgen control that modulates Sertoli cell functions that are essential for the process of spermatogenesis. PModS has a more dramatic effect on Sertoli cell differentiated functions in vitro than any regulatory agent previously shown to influence the cell, including FSH. Investigation of the actions of PModS on a molecular level have used transferrin expression as a marker of Sertoli cell differentiation. PModS was found to stimulate transferrin gene expression while having no effect on transferrin mRNA stability. The ability of PModS to elevate transferrin mRNA levels was inhibited by cycloheximide. Therefore, the actions of PModS require ongoing protein synthesis and appear to be indirectly mediated through trans-acting early event genes. PModS was found to dramatically increase mRNA levels for c-tos, but had no effect on c-jun mRNA levels. The c-fos mRNA levels increased transiently within a few minutes to a maximal level of stimulation at 1 h and returned to basal levels within 6 h. The rise in c-fos mRNA preceded the elevation in transferrin mRNA, which started to increase at 2 h to a maximum level between 6-12 h that was maintained at high levels for several days in cell culture. Treatment of Sertoli cells with an antisense c-fos oligonucleotide was found to inhibit the actions of PModS on transferrin expression. Combined results support the hypothesis that PModS acts indirectly through transcription factors (e.g. c-fos) to induce Sertoli cell differentiated functions (e.g. transferrin expression). Therefore, PModS appears to act as a differentiation-type factor to promote and maintain optimal Sertoli cell function.