Who watches the watchmen? WNT responsive stem cells and the regulation of their niche ligands

Multicellular organisms rely on versatile and robust cell-cell communication mechanisms to control tissue morphogenesis and homeostasis. Remarkably, a limited number of evolutionary conserved developmental signalling pathways is used in many different biological contexts, with different outcomes depending on time and place of their activity. Among these, the WNT signalling pathway controls a myriad of biological processes, balancing cell proliferation and differentiation throughout embryonic development and postnatal life in all metazoans.
There is a clear knowledge gap in our understanding of the spatiotemporal regulation of WNT signalling (or: the ‘when’ and ‘where’ of its activity) and what this means for stem cell regulation and tissue homeostasis. This thesis addresses this outstanding question from different angles. To study WNT signalling from the stem cell’s perspective we developed and characterized a novel mouse model that allows spatiotemporal imaging of the endogenous expression of Axin2, a canonical WNT reporter gene, in vivo and in vitro. In combination, we developed a multicolour lineage tracing mouse model to better study stem cell dynamics and directly visualize cell-cell interactions. To study the regulation of WNT ligands from the niche cell’s perspective we provide an in-depth framework for the epigenetic regulation of several WNT ligands in the mammary gland. Given that dynamic yet tight patterns of WNT gene expression have been observed, equally tight regulatory control mechanisms must exist. This process is poorly understood, yet is critical in the spatiotemporal control of WNT responsive stem cell activation and population size.