Regulation of pituitary progenitor differentiation by b-catenin

Abstract

The pituitary gland is a critical organ that is necessary for many physiological processes, including growth, reproduction, and stress response. The secretion of pituitary hormones from specific cell types regulates these essential processes. Pituitary hormone cell types arise from a common pool of pituitary progenitors, and mutations that disrupt the formation and differentiation of pituitary progenitors result in hypopituitarism. Canonical WNT signaling through CTNNB1 (b-catenin) is known to regulate the formation of the POU1F1 lineage of pituitary cell types. When b-catenin is deleted during the initial formation of the pituitary progenitors, Pou1f1 is not transcribed, which leads to the loss of the POU1F1 lineage. However, when b-catenin is deleted after lineage specification, there is no observable effect. Similarly, the generation of a b-catenin gain-of-function allele in early pituitary progenitors or stem cells results in the formation of craniopharyngiomas, whereas stimulating b-catenin in differentiated cell types has no effect. PROP1 is a pituitary-specific transcription factor, and the peak of PROP1 expression coincides with a critical time point in pituitary organogenesis—that is, after pituitary progenitor formation but before lineage specification. We used a Prop1-cre to conduct both loss- and gain-of-function studies on b-catenin during this critical time point. Our results demonstrate that pituitary progenitors remain sensitive to both loss and gain of b-catenin at this time point, and that either manipulation results in hypopituitarism.