Abstract
Leydig cells represent the steroidogenic lineage of mammalian testis, which produces testosterone. Genetic evidence indicates the requirement of Notch signaling in maintaining a balance between differentiated Leydig cells and their progenitors during fetal development. In primary Leydig cells, Notch1 expression decreases with testicular development, while the expression of its ligand, Jagged1, remains relatively unchanged, suggesting that the roles of Jagged1 extend beyond Notch signaling. In addition, Jagged1 is known to be processed into its intracellular domain, which then translocate to the nucleus. In this study, we investigated the effect of Jagged1 intracellular domain (JICD) on steroidogenesis in Leydig cells. The independent overexpression of JICD in MA-10 Leydig cells was found to inhibit the activity of cAMP-induced Nur77 promoter. In addition, JICD suppressed Nur77 transactivation of the promoter of steroidogenic genes such as P450scc, P450c17, StAR, and 3β-HSD. Further, adenovirus-mediated overexpression of JICD in primary Leydig cells repressed the expression of steroidogenic genes, consequently lowering testosterone production. These results collectively suggest that steroidogenesis in testicular Leydig cells, which is regulated by LH/cAMP signaling, is fine-tuned by Jagged1 during testis development.
Highlights
Leydig cells represent the steroidogenic lineage in the testis and drive male-specific development of germ cells and secondary sex differentiation by producing the male sex hormone testosterone
Jagged1 intracellular domain (JICD) overexpression inhibited Nur77-induced Nur77-target promoters, such as Nur77 response element (NurRE), NGF1-B response element (NBRE), P450c17, steroidogenic acute regulatory (StAR), and 3β-hydroxysteroid dehydrogenase (3β-HSD), in a dose-dependent manner (Fig 5A and 5B). These results suggest that JICD can independently repress Nur77 transactivation, resulting in the downregulation of steroidogenic genes in testicular Leydig cells
JICD, as we identified, represses the activity of Nur77 promoter, and it exerts a similar action on its target gene promoters
Summary
Leydig cells represent the steroidogenic lineage in the testis and drive male-specific development of germ cells and secondary sex differentiation by producing the male sex hormone testosterone. Progenitor cells in the developing testis, whose population is maintained by active Notch signaling, give rise to fetal Leydig cells. Notch signaling restricts fetal Leydig cell differentiation by promoting progenitor cell fate. The inhibition of Notch signaling or deletion of its downstream target, Hes, results in an increase in the number of mature Leydig cells [1]. The Notch ligand, Jagged, is an important regulator that maintains fetal Leydig progenitors in the undifferentiated state, which is guided by the level of interstitial testosterone [2]. Notch is a transmembrane receptor known to mediate intercellular communication required for cell fate determination, stem cell maintenance, and differentiation [3]. Subsequent to ligand binding, Notch is activated by γ-secretase-dependent proteolysis to release the Notch
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