The pituitary gland contains five different cell types that are specialized in hormone production. Understanding the mechanism of cell specification is important because many body functions depend on it. Genetically engineered mice have proven the roles of several transcription factors and signaling molecules, and the correspondence with human pituitary disease is outstanding. We proved that the homeodomain transcription factor PITX2 has a dosage dependent role in development of the pituitary primordium and in activation of lineage specific transcription factor genes. In humans, PITX2 mutations are a cause of Rieger syndrome and isolated growth hormone deficiency. We propose to test the role of PITX2 in maintenance of differentiated functions of specialized pituitary cells by cell specific deletion in mice. The role of GATA2, a downstream target of PITX2, will be tested using a conditional null allele of Gata2. FOXL2 is a forkhead transcription factor that is one of the earliest markers of differentiated cells in the developing pituitary gland, and it activates gonadotropin releasing hormone receptor transcription. Humans haploinsufficient for FOXL2 have eye defects and premature ovarian failure. We propose that FoxI2 has roles in regulating the growth of committed anterior pituitary cells during development, in the function of mature gonadotropes, and in susceptibility to pituitary tumors. We will explore these ideas by characterizing Foxl2 expression, placing it in the genetic hierarchy of known transcription factors, and analyzing the consequences of an inducible loss of function allele in mice. Our understanding of pituitary cell specification would be advanced if we had markers to identify specialized cells prior to terminal differentiation and activation of hormone gene transcription. To generate such markers we propose to compare the transcriptomes of pituitary cell types using transgenic technology to mark cells for purification and gene array analysis. Transcripts unique to each differentiated cell type will be identified by bioinformatics and verified experimentally. During the proposed grant cycle we will have defined the roles of three pituitary transcription factors using well-established methods and initiated a new approach to studying cell specification. We expect that these studies will provide valuable insight for understanding the etiology of human pituitary hormone deficiency diseases and characterization of pituitary adenomas. ? ?
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