International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


Camper SA, Ward RD, Brinkmeier ML, Nasonkin IO, Vesper AH, Potok MA, Stone BM, Beuschlein F, Suh H, Hammer GD, Raetzman LT

University of Michigan Medical School, Ann Arbor, MI, United States

The Prophet of PIT1 (PROP1) gene was discovered 8 years ago.  Recently animal studies have revealed the mechanism of Prop1 action and provide an explanation for the unusual clinical features in humans with PROP1 mutations. Lesions in PROP1 are the most common known cause of autosomal recessive hypopituitarism in humans.  GH, TSH, PRL, LH and FSH are usually deficient, and hypocortisolism occasionally develops.  Surprisingly, some patients initially have normal pituitary size or hyperplasia that resolves to hypoplasia later in childhood.  We investigated the mechanism of PROP1 action using mice with altered PROP1 levels, including the spontaneous mutant known as Ames dwarf (Ser83Pro), a genetically engineered null mutant that deletes the homeodomain of this transcription factor, and a transgenic over-expressor of PROP1.  Many features of the human patients are mimicked in PROP1 deficient mice. Adult mutant mice are consistently deficient in GH, TSH, PRL, LH and FSH, although there is no evidence of acquired ACTH deficiency through the first year of life. The genetic background has a profound influence on the mutant phenotype, which can include lethal respiratory distress syndrome, juvenile wasting associated with hypoglycemia, or viable adult dwarfism.  PROP1 expression peaks in mice during early embryonic development and decreases to barely detectable levels by birth.  Despite the transient, fetal-specific expression, the total mass of the pituitary prirmordium is nearly indistinguishable in normal and PROP1 deficient mice until a week after birth.  The mutant mice develop pituitary hypoplasia eventually because proliferating progenitor cells are unable to migrate ventrally into the anterior lobe of the organ.  This initially results in dorsal overgrowth of undifferentiated cells, which resolves through enhanced apoptosis in 1-2 week old mice.  This appears analogous to the hyperplasia and degeneration of the pituitaries of some human patients.  We expect that progenitor cells fail to migrate and differentiate because mutants are unable to restrict expression of the HESX1, TLE3, AES repressor complex and unable to activate expression of NOTCH2 and PIT1.  Persistent expression of the repressor complex is sufficient to block differentiation, misexpression of NOTCH2 is sufficient for disruption of gonadotrope differentiation, and PIT1 is required for specification of somatotropes, thyrotropes and lactotropes.  Interestingly, both reduced and elevated expression of Prop1 disrupt gonadotrope function, suggesting that a specific level of PROP1 may be critical for normal pituitary function.  In summary, the Prop1 mutant mice are valuable tools for understanding the mechanism of PROP1 action. 

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