The pituitary gland regulates development and function of many organs to control growth, response to stress, fertility and homeostasis. Congenital pituitary hormone deficiencies are common, occurring in approximately one out of every 4000 live births. Hormone deficiency can exist as loss of a single hormone or combined pituitary hormone deficiency (CPHD). Mutations in a dozen genes have been identified as causes of CPHD, but the etiology of half of cases remains unknown. The long-term goal of the proposed studies is to identify the genes that, when mutated, cause pituitary hormone insufficiency and determine the mechanism of action of those genes. To expand the molecular diagnoses for pituitary hormone insufficiency, we have focused on a family of transcription factors referred to as forkhead factors. Forkhead factors are essential for diverse developmental processes and mutations in the genes encoding these factors are responsible for a number of human developmental disorders. Our previous studies have identified the forkhead transcription factor, Foxo1, as a candidate gene for pituitary hormone insufficiency. FOXO1 is expressed in somatotrope cells at e18.5 and in adult males and females. Mice lacking Foxo1 in the pituitary have a drastically reduced number of growth hormone-containing cells, suggesting that Foxo1 is required for normal growth hormone (GH) production. It is important to investigate the mechanisms of FOXO1 regulation of GH production because of the critical role of GH in growth, healthy metabolism, and heart function. We hypothesize that FOXO1 regulates GH production beginning early in development by regulating expression of the growth hormone gene or upstream regulators that control GH production. Our hypothesis will be tested by the following aims: 1) Determine the mechanism by which FOXO1 regulates GH production.
This aim will employ luciferase reporter assays and chromatin immunoprecipitation assays to determine which genes are directly regulated by FOXO1. 2) Determine when Foxo1 is required for GH production.
This aim will analyze GH production at early stages of development in mouse embryos that have the Foxo1 gene excised from the pituitary. Our expertise in both forkhead transcription factor function and pituitary development places us in a unique situation to address this fundamental question. The knowledge generated by these studies will further this field by exploring the mechanism of action of a candidate gene for pituitary hormone deficiency and by adding to our knowledge of pituitary organogenesis.
Birth defects that affect pituitary gland development and function can cause growth retardation, sex reversal and/or infertility, and mental retardation. Several genes are known to contribute to these birth defects;however the genes responsible for the majority of cases have yet to be identified. Our goal is to identify genes that are important fr pituitary gland development and determine how they contribute to birth defects.