Molecular Control of Pituitary Development and Tumorigenesis

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Pituitary adenomas are among the most prevalent of human tumors, affecting over 15% of the population in the United States. However, it is not yet known what regulates the division of endocrine cells in adults. Hedgehog (Hh)/Gli and Fgf-mediated cell-cell signaling play critical roles in pituitary development in the embryo, a requirement that has been conserved across vertebrate species from fish to humans. We have shown that Hh/Gli signaling plays a role in controlling the number and position of endocrine cell types in the embryo. Little is known about the cellular and molecular mechanisms by which Hh acts in the pituitary, or how these signaling systems continue to influence endocrine cell differentiation and proliferation post-embryonically. Our goal is to understand the mechanisms by which Hh induces and functionally patterns the vertebrate pituitary in the embryo and to determine how Hh/Gli signaling influences pituitary growth post- embryonically. In Aim #1 we seek to determine the embryonic origin of the two sub-domains of the adenohypophysis and determine whether Hh/Gli signaling is directly required in placodal cells, a crucial step toward understanding the cellular and molecular mechanisms that induce and pattern the pituitary gland. The goal of Aim #2 is to characterize and quantify endocrine cell proliferation in the larval pituitary and determine how Hh/Gli signaling regulates endocrine cell numbers post-embryonically. These studies are designed to provide insight into how the ordered complexity of this tissue arises, how different endocrine cell types are generated, and how pituitary growth and differentiation are regulated. Answering these questions is important, not least because many diseases have their origins in embryonic development. Errors in Hh signaling at this time, if not corrected, can develop into medical conditions such as holoprosencephaly or endocrine dysfunction, including dwarfism and hypopituitarism. Because Hh inhibitors are being used now to treat several other human tumors, this work may help provide the molecular background needed to bring similar treatments to patients with pituitary adenomas. Comment [MB1]: I assume that stat is in the US? I would insert US here, given that you are applying for PHS money.