Cell signalling aimed at regulating cell proliferation

Stem cell mitotic response to damage in old and young Drosophila melanogaster

Adult stem cells maintain tissues by dividing asymmetrically to produce both stem cells and differentiating daughter cells that replenish lost or dying cells to ensure the integrity of the organism. All cells within an organism, including stem cells and their progeny, can be challenged by cellular stresses that lead to cell death. Regeneration after cell death following trauma allows regrowth and repair. Research in many organisms has shown that it is the apoptotic cells themselves that can mediate complex intracellular signals and release complex intercellular signals to their surviving neighbours that stimulate cell proliferation, which is known as “Apoptosis-Induced Proliferation” (AIP). AIP is mediated within the apoptotic cells by the apoptotic signaling cascade along with p53 and Jnk signaling and results in the dying cells secreting mitogens to directly stimulate cell proliferation.

To date most of the research on AIP has focused on proliferating and differentiating adult tissues. Despite their centrality to the homeostasis of many adult tissues almost nothing is known about AIP in stem cell populations. The aim of this project is to identify how cell signaling is orchestrated to regulate AIP in Drosophila testis stem cells, how this contributes to the homeostasis of young and old tissues and how this could be abrogated genetically to ameliorate or reverse the negative effects of ageing on AIP.

Specific objectives:

• Identify the signals that are required for dying cells to cause the germ line stem cells and their progeny cells to divide more after damage by determining mitotic index of all cell in testis in which putative cell signaling molecules have been knocked out at various times after apoptosis is activated by irradiation.
• Identify the signals that are required in stem cells to receive the AIP signal from dying cells by knocking out putative cell signaling molecules in stem cells and determining their mitotic index at various times after apoptosis is activated by irradiation.
• Identify which signals are lost in older cell population whose re-introduction through ectopic expression could re-establish AIP in older cells by determining mitotic index of all cell in testis in which putative cell signaling molecules have been knocked out at various times after apoptosis is activated by irradiation in 30 day old flies. Identified pathways would be re-introduced into 30 day old flies using ectopic expression by the inducible Gal4-SWITCH system and mitotic index of cell types determined in flies at various times after apoptosis has been inducted by irradiation.

Publications

• Progeria Research Day at Brunel University. Bridger JM, Eskiw CH, Makarov EM, Tree D, Kill IR.; Nucleus. 2011 Nov-Dec;2(6):517-22. doi: 10.4161/nucl.2.6.17605. Epub 2011 Nov 1. Review.
• Towards a Drosophila model of Hutchinson-Gilford progeria syndrome. Beard GS, Bridger JM, Kill IR, Tree DR. Biochem Soc Trans. 2008 Dec;36(Pt 6):1389-92. doi: 10.1042/BST0361389.