Foxo1 Is Required for Normal Somatotrope Differentiation

Endocrinology. 2016 Nov;157(11):4351-4363. doi: 10.1210/en.2016-1372. Epub 2016 Sep 15.


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 (Foxo1Δpit). 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, Foxo1Δpit 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 Foxo1Δpit mice. Foxo1Δpit 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.

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Embryo, Mammalian / metabolism
  • Exons / genetics
  • Female
  • Follicle Stimulating Hormone / genetics
  • Follicle Stimulating Hormone / metabolism
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / metabolism*
  • Immunohistochemistry
  • In Situ Hybridization
  • Luteinizing Hormone / genetics
  • Luteinizing Hormone / metabolism
  • Mice
  • Pituitary Gland / cytology
  • Pituitary Gland / metabolism
  • Pregnancy
  • Somatotrophs / cytology*
  • Somatotrophs / metabolism*
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Time Factors


  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Luteinizing Hormone
  • Follicle Stimulating Hormone