PhD Defence: Duncan John Mackay

Title: Investigating the role of Pvf1-Pvr signalling during regenerative stem cell migration

Supervisor: Ditte Skovaa Andersen

Assessment committee:
Kim Rewitz (Chair), Department of Biology, University of Copenhagen
Irene Miguel-Aliaga, Francis Crick institute, London
Dr. Kyra Campbell, School of Biosciences, University of Sheffield, UK

Abstract
In response to tissue damage, stem cells must dynamically respond to repopulate the damaged area. For larger areas of damage, this requires the stem cells to orientate and migrate, before dividing and differentiating to restore epithelial integrity. The Drosophila midgut presents a well-suited model to study the first portion of this response, as many of the mechanisms underpinning the downstream processes, of division and differentiation, have been elucidated over the past 20 years. In addition, recent work has established sophisticated ex vivo live imaging techniques that enable in depth investigation of the initial response to damage for the first time. In this PhD thesis, we identify Pvf1-Pvr signalling as a crucial regulator of regenerative cell migration in the adult Drosophila midgut. We show at high temporal resolution that stem cells break from quiescence, forming actin rich lamellipodia, before moving to damaged areas, and that Pvr signalling is required for this process. We further demonstrate that Pvf1 from the surrounding vasculature, is required for directional migration, with stem cells migrating randomly in its absence. We additionally present the results of an unbiased receptor screen, for conserved receptors in the midgut niche, where we identified candidate genes which regulate the regenerative response to infection. The framework we have established here, to study the initial response to epithelial damage, can serve as an effective experimental platform to study these candidates in future work.