Cheung, L; (2013) Genetic Manipulation of the Wnt and Notch Signalling Pathways in the Pituitary Gland in Vivo. Doctoral thesis , UCL (University College London).

Abstract

The Wnt and Notch signal transduction pathways are two important regulators of pituitary organogenesis. Wnt signalling regulates maintenance, proliferation and differentiation of the progenitor pool during early pituitary development, whilst Notch signalling prevents the premature specification of endocrine cell-types. Components of the Wnt and Notch pathways are downregulated in the pituitary as development proceeds. Furthermore, their expression is detected in the mature, adult gland. Our studies investigate the role of Wnt and Notch signalling in the adult and developing pituitary gland through genetic manipulation of signalling mediators in vivo. We investigate the function of Wnt signalling in committed POU1F1-expressing cells through the conditional deletion of the canonical Wnt signalling mediator Ctnnb1. We find that the loss of β-catenin from adult POU1F1-expressing cells does not dramatically affect adult pituitary hormone production, suggesting that the canonical Wnt pathway is not required for normal function of POU1F1- expressing cells. In parallel, we studied the role of Notch signalling in POU1F1-expressing cells through conditional overexpression of the constitutively activated Notch receptor. We find that, in contrast to previous studies, constitutive Notch signalling in POU1F1-expressing cells also does not affect their differentiation or function. At the same time, we do not find any pituitary-specific functions for the Notch signalling ligand Delta-like 1 homologue (DLK1). We therefore conclude that downregulation of Notch signalling is not required for normal development or function of POU1F1-expressing cells. Finally, our studies investigated the temporal specificity of Notch signalling throughout pituitary organogenesis through constitutive Notch activation in celltypes ranging from early progenitors to committed endocrine cells. Our results indicate that Notch signalling is especially important for specification of embryonic progenitors into melanotrophs. We also find evidence suggesting non-redundant functions for NOTCH receptor paralogues, and we ultimately propose a model for Notch signalling function during pituitary development.

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