The pituitary gland contains individualized cell types that specialize in the production of individual hormones. Understanding the mechanisms that underlie the transition from proliferation to cell differentiation is important because many body functions depend on it. Genetically engineered mice have proven the roles of several transcription factors and signaling molecules in differentiation, and the correspondence with human pituitary disease is outstanding. During the last grant cycle we demonstrated the roles of four transcription factors in pituitary development and function. We proved that the homeodomain transcription factor PITX2 has a dosage dependent role in expansion of the pituitary primordium and activation of gonadotrope-specific cre transcription factors. We created a gonadotrope-specific cre strain and used it for cell specific deletion of PITX2. These mice had normal onset of puberty and fertility, suggesting other genes compensate for PITX2 deficiency in mature gonadotropes. PITX2 is necessary for expression of the Zn finger transcription factor GAT A2 in pituitary development. We developed a floxed allele of GATA2 and a pituitary specific strain to show that GAT A2 is important for optimal gonadotrope and thyrotrope function but not required for cell fate. We discovered that the forkhead transcription factor, FOXL2, is co-expressed with a-subunit in gonadotropes and thyrotropes, and it is sufficient to generate a-subunit expression in transgenic mice. We investigated the mechanism whereby LHX3 deficiency cases pituitary hypoplasia and failed cell specification. Interestingly, LHX3 is necessary to prevent apoptosis and stimulate expression of Notch2, which regulates exit from the cell cycle and differentiation. Without this, dorsal cells differentiate into cell fates normally restricted to ventrally localized cells. Taken together our analysis of these four transcription factors has advanced our understanding of the genetic hierarchy that controls pituitary organogenesis and the mechanisms that underlie congenital pituitary hypoplasia. During the next grant cycle we propose to test the hypotheses that Aim 1) the temporal and spatial expression pattern of cell cycle regulators is affected in mutant mice with pituitary hypoplasia or hyperplasia, resulting in abnormalities in the transition from precursor cell proliferation to differentiation, and Aim 2) PITX2 is important for thyrotrope maintenance and function. These studies will integrate molecular mechanisms involving cell cycle regulators, critical transcription factors, and selected cell-signaling pathways in the control the transition from proliferation to differentiation in normal development. This information will be informative for identifying the basis for human pituitary diseases including congenital hormone deficiencies and common adenomas.
The pituitary gland is known as the master gland because it controls the function of many other organs including bone growth, lactation, stress response involving adrenal glands, testes and ovarian functions, thyroid gland, and maintenance of homeostasis. There are two main forms of pituitary dysfunction: lack of hormone production in newborns and young children due to a congenital birth defect and loss of hormone production in adults due to pituitary adenoma formation. While hormone replacement therapy can be successful and adenomas can be treated pharmacologically or with surgery, not all patients are helped by these methods. We propose to study the genes that regulate pituitary cell growth and differentiation, which are precisely the processes that are defective in affected children and adults. We also propose to take the lessons learned from these studies in mice and enhance the development of stem cells into hormone producing cells. Together we anticipate that this information could lead to better understanding of the etiology and better treatments for pituitary disease in humans.
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