Unique Effects of PROP1 and POU1F1 on Pituitary Progenitor Development, Proliferation and Differentiation

MARÍA INÉS PÉREZ MILLÁN; BRINKMEIER ML; CLAUDIA VEIGA CHANG; LUCIANI CARVALHO; CAMPER SA

Chicago, IL

Congreso; The Endocrine Society´s Annual Meeting; 2014

Multiple pituitary hormone deficiency (MPHD) can be caused by mutations in several pituitary transcription factor genes in mouse and man, including Prop1, Pou1f1, Hesx1, Sox2 and other genes. Prop1 is expressed briefly during embryonic development and early postnatal life in mice, and it is necessary for repression of Hesx1 expression and activation of Pou1f1 (1). PROP1 mutations cause progressive hormone deficiency in humans, affecting all lineages, while POU1F1 mutations cause MPHD involving TSH, GH and PRL production exclusively. We hypothesize that PROP1?s role is in progenitor transition to differentiation and POU1F1 has a later role restricted to lineage-specific cell specification. To test this hypothesis we examined the effect of both mutations on expression of stem cell markers and on the quantity of progenitor colony forming cells (PCFC) (2). Prop1 mutant mice have elevated expression of Sox2 in the postnatal pituitary gland, while similar levels of expression were detected in Pou1f1 mutants, supporting the hypothesis. Both mutants can generate PCFCs in culture that express stem cell markers including Sox2, Sox9 and Gfra2. Surprisingly, pituitaries from either mutant contain more PCFC than wild types, and they proliferate at a more rapid rate. Both mutations exert effects on the developmental profile of PCFC. Normally PCFC decrease as animals develop after birth, but PCFC peak in Prop1 mutants between P7 and 13, and Pou1f1 mutant PCFC accumulate at later ages during adulthood. This is consistent with the fact that Prop1 is upstream of Pou1f1 in the genetic hierarchy and several days earlier than Pou1f1, and these results imply that Pou1f1 has an unexpected role in PCFC development and/or function. PCFC from Prop1 mutant mice have a different morphology than Pou1f1 mutants and wild type derived colonies. RNA-Seq experiments identify genes unique to each mutant genotype and suggest candidate genes to explain the differences in PCFC numbers, morphology, and proliferation rates. These results support the idea that Prop1 is necessary to promote the transition of progenitors to differentiation and reveal an unexpected role for Pou1f1 in PCFC. Understanding the molecular mechanisms that underlie PCFC development and function is an important starting point for considering effective therapeutic treatments for MPHD.