Ames (df) dwarf mice provide an entree for understanding the molecular events that regulate pituitary gland organogenesis. Mutants exhibit panhypopituitarism, or multiple pituitary hormone deficiency, failing to produce adequate amounts of prolactin, growth hormone, thyroid stimulating hormone, or gonadotropins. A missense mutation in the homeodomain of the transcription factor Propi is responsible for the defect. This partial loss of function mutation affects development of the pituitary gland early in organogenesis, causing cytodifferentiation failure of several cell types that ultimately results in a hypocellular anterior pituitary lobe. PROP1 mutations cause multiple pituitary hormone deficiency in humans as well, although the phenotype is variable, occasionally involving loss of adrenocorticotropin production. Using genetic engineering in mice we generated both null and gain of function alleles of Prop. Homozygotes for the null allele exhibit lethality with 50% penetrance, which may result from adrenal insufficiency, as observed in some human pedigrees with PROP1 mutations. Propi expression is normally restricted to a short window of pituitary development, and prolonged expression causes transient hypogonadism and delayed puberty due to delayed differentiation of pituitary gonadotropin producing cells. In addition, mice with this gain of function allele develop adult onset hypothyroidism and have increased risk of pituitary adenomas. Pituitary adenomas are the most common type of intracranial tumor in humans, although little is known about the genetic changes that lead to adenoma formation. We have delineated many of the sequential steps in the commitment process of organogenesis, placing Prop 1 in the genetic hierarchy relative to several other critical homeobox genes. During the next grant cycle we propose to characterize the Propi null allele to discover the basis for the failure of cytodifferentiation. We will dissect the interactions of Propi with pituitary transcription factors and secreted signaling molecules that are important in early development using genetics, explant and cell culture, DNA sequence analysis, and differential expression analysis. These studies will expand our understanding of pituitary organogenesis and tumorigenesis.
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