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Role of Prophet of Pit1 (PROP1) in Gonadotrope Differentiation and Puberty

Department of Human Genetics (A.H.V., S.A.C.), University of Michigan, Ann Arbor, Michigan 48109-0638; and Department of Molecular and Integrative Physiology (L.T.R.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

Address all correspondence and requests for reprints to: Sally A. Camper, Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109-0618. E-mail: scamper{at}umich.edu.

The prophet of Pit1 (PROP1) gene is essential for normal gonadotropin production in both humans and mice. Transgenic mice that overexpress PROP1 in gonadotropes and thyrotropes have transient hypogonadotropic hypogonadism and increased risk of pituitary adenomas. Here we report a temporal study of pituitary gonadotrope terminal differentiation and hypogonadism, delayed onset of puberty, and transient growth insufficiency in the transgenic males. The Prop1 transgenic mice recover from their abnormalities and exhibit normal size and fertility at 3 months. The relatively normal expression pattern of GnRH receptor (Gnrhr) suggests that the pituitary gonadotrope cell lineage is appropriately specified, but the ability to synthesize LH and FSH is impaired by excess PROP1. We report no obvious abnormalities in expression of the transcription factors early growth response 1, NR5A1, GATA2, TBX19, and NR0B1, or the TGFß pathway members including activin, inhibin, and activin receptors. Thus, overexpression of PROP1 may influence gonadotrope development by a novel mechanism. Microarray analysis identified the inhibitory transmembrane receptor gene Klrg1 and the protease gene Prss28 as candidates for involvement in this process. We hypothesize that variation in PROP1 expression could affect the growth spurt and the onset of puberty in humans.

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