The interplay between FOXO1 and glucocorticoid signaling in promoting the terminal differentiation of somatotropes

Abstract

Glucocorticoids play a pivotal role in terminal differentiation of pituitary somatotropes. However, the mechanisms for this remain poorly understood. Here we demonstrate that loss of the forkhead transcription factor, FOXO1, severely impairs glucocorticoid-induced expression of the gene encoding growth hormone (Gh1) both in vitro and in vivo. The mechanism appears to involve glucocorticoid induction of Foxo1 expression, nuclear localization, and increased binding associated with the Gh1 gene. An additional mechanism includes stabilization of the glucocorticoid receptor, NR3C1, possibly through FOXO1 induction of the chaperone protein, HSP90. Together these data suggest that glucocorticoid signaling and FOXO1 cooperate to promote Gh1 expression, an essential aspect of somatotrope terminal differentiation.