Foxo1 Is Required for Normal Somatotrope Differentiation

Abstract

The etiology for half of congenital hypopituitarism cases is unknown. Our long-term goal is to expand the molecular diagnoses for congenital hypopituitarism by identifying genes that contribute to this condition. We have previously shown that the forkhead box transcription factor, FOXO1, is present in approximately half of somatotropes at embryonic day (e) 18.5, suggesting it may have a role in somatotrope differentiation or function. To elucidate the role of FOXO1 in somatotrope differentiation and function, Foxo1 was conditionally deleted from the anterior pituitary (Foxo1). Uncommitted progenitor cells are maintained and able to commit to the somatotrope lineage normally based on the expression patterns of Sox2, a marker of uncommitted pituitary progenitors, and Pou1f1 (also known as Pit1), which marks committed progenitors. Interestingly, Foxo1 embryonic mice exhibit delayed somatotrope differentiation as evidenced by an almost complete absence of GH immunoreactivity at e16.5 and reduced expression of Gh at e18.5 and postnatal day (P) 3. Consistent with this conclusion, expression of GHRH receptor, a marker of terminally differentiated somatotropes, is significantly reduced at e18.5 and P3 in the absence of FOXO1. The mechanism of FOXO1 regulation of somatotrope differentiation may involve the basic helix-loop-helix transcription factor, Neurod4, which has been implicated in somatotrope differentiation and is significantly reduced in Foxo1 mice. Foxo1 mice do not exhibit growth defects, and at P21 their pituitary glands exhibit a normal distribution of somatotropes. These studies demonstrate that FOXO1 is important for initial somatotrope specification embryonically but is dispensable for postnatal somatotrope expansion and growth.

Single-cell transcriptomics identifies divergent developmental lineage trajectories during human pituitary development

“…Previous studies have shown that mutation of Neurod4 in mice leads to almost completely lack of GHRHR expression and markedly decrease in GH expression 21 , 37 . Mutation of Foxo1 in mice also results in delayed somatotrope differentiation 38 . Notably, we found that NEUROD4 was clearly activated in Pro.PIT1_all cells in comparison with the stem cells (logFC = 1.6, P = 1.3E–18, Fig.…”

Natural and molecular history of prolactinoma: insights from aPrlr-/– mouse model

“…FOXO1 (forkhead box transcription factor 1) plays a role in normal somatotrope differentiation as well as gonadotrope function. However, no role of this transcription factor has yet been described in lactotroph cell or in pituitary tumorigenesis [ 39 ]. That being said, it is worth mentioning that FOXO TFs are well-known targets of AKT1, and important regulators of cell-cycle and proliferation in many cell types.…”

Transcriptomic Profiles of Normal Pituitary Cells and Pituitary Neuroendocrine Tumor Cells

“…Among other genes, scRNA-seq shows upregulation of FOXO1 and CEBPD in fetal human somatotrophs [14]. Pituitary-specific double knock-out of FOXO1 in mice results in delayed terminal differentiation of somatotrophs and reduced expression of GHRHR [22]. Additionally, FOXO1 knock-out results in decreased expression of NEU-ROD4.…”

“…Additionally, FOXO1 knock-out results in decreased expression of NEU-ROD4. Thus, FOXO1 may be an upstream regulator of NEUROD4 during somatotroph differentiation [22]. However, this mechanism is still unclear, as scRNA-seq in human fetal somatotrophs suggests that NEUROD4 is upregulated before FOXO1 expression [14].…”