Postnatal Expression of PROP1 Regulates the Transition of Progenitors to Differentiating Cells

BRINKMEIER ML; MARÍA INÉS PÉREZ MILLÁN; CHEUNG L; CAMPER SA

Chicago, IL

Congreso; The Endocrine Society´s Annual Meeting; 2014

Proper size and composition of the mouse anterior pituitary is achieved through two waves of pituitary growth (1,2). Early proliferation, migration, and differentiation of progenitor cells between embryonic day 12.5 (e12.5) and e14.5 in mice is required to establish the initial pools of anterior pituitary cells. A subset of these cells retain their proliferative capacity and drive a second wave of pituitary growth after birth, expanding the populations of differentiated cells to their proper proportions. Both Prop1df/df and Pou1f1dw/dw mutants lack anterior pituitary somatotropes, thyrotropes, and lactotropes resulting in dwarfism and hypothyroidism, but the pituitaries of Prop1 mutants exhibit a unique dysmorphology and earlier onset hypopituitarism relative to Pou1f1 mutants (3). This may be explained by the differentially regulated genes unique to Prop1 and Pou1f1 mutants (4). We hypothesized that Prop1 regulates the transition of progenitors to differentiated cells. To explore this idea we examined the effect of both mutations on expression of selected transcription factors, cell cycle regulators and signaling pathways from e12.5 Rathke?s Pouch through postnatal day 7 (P7) pituitary. We discovered a second wave of Prop1 expression after birth suggesting it plays a role during both embryonic and postnatal growth. During embryogenesis expression of Notch2 (5) and the transitional cell marker cyclin E (6), are reduced in Prop1 mutants, but they do not appear to depend on Prop1 or Pou1f1 postnatally. Pituitary stem cells or progenitors are marked by several transcription factors including the SOXB family member SOX2. A modest increase (~2 fold) in postnatal Sox2 expression is evident in Prop1 mutants, consistent with the idea of a transitional block. Another SOXB transcription factor exhibits dramatically increased expression (~50-100 fold), specifically in Prop1 mutants between P3 and P7. Normally this gene is silenced before birth, in contrast to the essentially uniform expression of Sox2 throughout wild type embryonic and postnatal pituitary development. Dynamic regulation of SOXB genes can influence the transition from progenitor to differentiated cells in other organ systems (7). In summary, we have discovered a potential role for Prop1 in postnatal expansion of the pituitary gland associated withelevated expression of progenitor markers and reduction in expression of transitional cell markers. In addition we identified a potential Prop1 target that may regulate the transition between progenitor proliferation and differentiation.