Persistent Prop1 expression delays gonadotrope differentiation and enhances pituitary tumor susceptibility

The 'paired'-like homeodomain transcription factor Prop1 is essential for t he expansion of the pituitary primordia and for the differentiation and/or function of the hormone-producing cells of the anterior pituitary gland. Pr op1 expression is normally extinguished before transcription of most differ entiation markers is initiated. We report that constitutive expression of P rop1 interferes with anterior pituitary cell differentiation and increases the susceptibility for pituitary tumors. The terminal differentiation of pi tuitary gonadotropes is delayed, resulting in transient hypogonadism and a delay in the onset of puberty. Thyrotrope differentiation occurs normally, but thyrotrope function is impaired resulting in mild hypothyroidism. Aged mice exhibit defects consistent with misregulation of pituitary cell prolif eration, including adenomatous hyperplasia with the formation of Rathke's c left cysts and tumors. Thus, silencing Prop1 is important for normal pituit ary development and function. These data suggest that gain-of-function muta tions in PROP1 could contribute to the most common human pituitary endocrin opathies and tumors.