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FOXO Transcription Factors Are Required for Normal Somatotrope Function and Growth
Caitlin E Stallings1, Jyoti Kapali1, Brian W Evans1
1Department of Physiology, Southern Illinois University, Carbondale, IL 62901, USA.
Abstract:
Understanding the molecular mechanisms underlying pituitary organogenesis and function is essential for improving therapeutics and molecular diagnoses for hypopituitarism. We previously found that deletion of the forkhead factor, Foxo1, in the pituitary gland early in development delays somatotrope differentiation. While these mice grow normally, they have reduced growth hormone expression and free serum insulin-like growth factor-1 (IGF1) levels, suggesting a defect in somatotrope function. FOXO factors show functional redundancy in other tissues, so we deleted both Foxo1 and its closely related family member, Foxo3, from the primordial pituitary. We find that this results in a significant reduction in growth. Consistent with this, male and female mice in which both genes have been deleted in the pituitary gland (dKO) exhibit reduced pituitary growth hormone expression and serum IGF1 levels. Expression of the somatotrope differentiation factor, Neurod4, is reduced in these mice. This suggests a mechanism underlying proper somatotrope function is the regulation of Neurod4 expression by FOXO factors. Additionally, dKO mice have reduced Lhb expression and females also have reduced Fshb and Prl expression. These studies reveal FOXO transcription factors as important regulators of pituitary gland function.
Insights
Forkhead box (FOXO) transcription factors regulate pituitary gland development and function. Deleting FOXO1 and FOXO3 in mice reduces growth hormone and IGF1 levels, impacting somatotrope function.
Area of Science:
- Endocrinology
- Developmental Biology
- Molecular Genetics
Background:
- Pituitary organogenesis and function are crucial for development and health.
- Hypopituitarism requires better therapeutic and diagnostic approaches.
- Forkhead box (FOXO) transcription factors are known regulators in various tissues.
Purpose of the Study:
- To investigate the role of FOXO1 and FOXO3 in pituitary development and function.
- To understand the molecular mechanisms of somatotrope differentiation and hormone production.
Main Methods:
- Conditional knockout mouse models were generated to delete Foxo1 and Foxo3 in the pituitary.
- Analysis included growth measurements, hormone level assessments (growth hormone, IGF1, LH, FSH, PRL), and gene expression studies (Neurod4).
Main Results:
- Deletion of both Foxo1 and Foxo3 (dKO) in the pituitary significantly reduced overall growth.
- dKO mice exhibited decreased pituitary growth hormone and serum IGF1 levels.
- Reduced expression of the somatotrope differentiation factor Neurod4 was observed in dKO mice.
- dKO mice showed reduced Lhb expression, with females also having reduced Fshb and Prl expression.
Conclusions:
- FOXO transcription factors are essential regulators of pituitary gland development and function.
- FOXO factors regulate somatotrope function, at least partly through controlling Neurod4 expression.
- These findings highlight FOXO factors as potential targets for understanding and treating pituitary disorders.
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