Congenital hormone deficiencies are common, occurring in approximately one in 4,000 live births. Pituitary hormone deficiency can consist of loss of a single hormone (isolated hormone deficiency) or several hormones (combined pituitary hormone deficiency). Absence of anterior pituitary hormones does not interfere with fetal viability, but are required for survival after birth, gonadal differentiation, and maturation of the fetal thyroid. Lesions in the transcription factors PITX1, PITX2, HESX1, LHX3, LHX4, TPIT, PROP1 and PIT1 lead to combined pituitary hormone deficiency in mice and humans. However mutations in these transcription factors account for only a fraction of congenital hormone deficiencies in humans. To identify additional factors that contribute to human congenital hormone deficiencies, we are investigating the forkhead transcription factor, FOXO1, which is important for the normal development of several organs. Mouse knockout models for Foxo1 result in embryonic lethality at embryonic day (e)10.5 due to vascular defects. Our objective is to investigate the contributions of FOXO1 to congenital pituitary hormone deficiency. We hypothesize that eliminating FOXO1 in the pituitary will cause hyperplasia and misorganization of the pituitary gland resulting in loss of hormone production and/or mis-specification of hormone-producing cell types. This hypothesis is based on the following observations. First, our preliminary results show that FOXO1 is present in nuclei of non-dividing pituitary cells starting at e14.5 when these cells are beginning to differentiate. Secondly, FOXO1 inhibits proliferation and regulates differentiation and migration of pancreatic 2-cells, myoblasts, adipocytes, and endothelial cells. To test this hypothesis we propose three specific aims:
Specific Aim 1. Determine the pituitary cell specificity for FOXO1 during development. We will perform immunohistochemistry for the hormones that mark the five pituitary cell types in combination with immunohistochemistry for FOXO1 on mouse embryonic tissue at e18.5.
Specific Aim 2. Investigate the requirement for Foxo1 in pituitary gland development and function. We will analyze pituitary glands from mouse embryos that have had Foxo1 expression eliminated in the pituitary gland (Foxo1 pit/-). We will assess pituitary morphology, analyze anterior pituitary hormone production, and measure cell proliferation and apoptosis.
Specific Aim 3. Place Foxo1 in the genetic hierarchy of pituitary gland developmental control. We will perform immunohistochemistry on Foxo1 pit/- mouse embryos for genes that are required during normal pituitary development. The knowledge generated by these studies will further this field by identifying a candidate gene for congenital pituitary hormone deficiency and by adding to our knowledge of how forkhead factor mutations cause birth defects. Our expertise in both forkhead transcription factor function and pituitary development places us in a unique situation to address this problem.
Pituitary hormones are essential for survival after birth and for the normal development of gonads and thyroid gland. The forkhead transcription factor, FOXO1, is essential for the normal development and function of muscle, blood vessels, and pancreas. The pattern of FOXO1 localization in the pituitary gland during development suggests a role for inhibiting cell division and regulating cell differentiation. Our objective is to determine the requirement of FOXO1 for normal pituitary development by analyzing the pituitary phenotype in mice that lack FOXO1 in the pituitary gland.
| Kapali, Jyoti; Kabat, Brock E; Schmidt, Kelly L et al. (2016) Foxo1 Is Required for Normal Somatotrope Differentiation. Endocrinology 157:4351-4363 |
| Calderon, Michael J; Ploegman, Adam G; Bailey, Brock et al. (2015) Loss of Foxm1 Results in Reduced Somatotrope Cell Number during Mouse Embryogenesis. PLoS One 10:e0128942 |
| Tran, Stella; Zhou, Xiang; Lafleur, Christine et al. (2013) Impaired fertility and FSH synthesis in gonadotrope-specific Foxl2 knockout mice. Mol Endocrinol 27:407-21 |
| Majumdar, Sreeparna; Farris, Corrie L; Kabat, Brock E et al. (2012) Forkhead Box O1 is present in quiescent pituitary cells during development and is increased in the absence of p27 Kip1. PLoS One 7:e52136 |
