The Transcription Factor Sob Maintains Intestinal Stem Cell Homeostasis to Delay Ageing

Abstract

Ageing is associated with physiological decline and disrupted tissue homeostasis, often driven by imbalanced stem cell activity. The Drosophila midgut serves as a powerful model for studying epithelial homeostasis and ageing as it exhibits many conserved hallmarks of regulation and deteriorating intestinal stem cell function with age. We have identified the transcription factor encoded by Sister of odd and bowl (Sob) as a conserved marker of intestinal stem/progenitor cells in homeostasis whose expression is lost with age. Premature downregulation of sob shortens lifespan while overexpression in the intestinal stem/progenitor cells is sufficient to extend lifespan, suggesting a critical role in maintaining homeostasis with age. At the cell and tissue level stem/progenitor knockdown and overexpression reveal that Sob maintains homeostasis by regulating both proliferation and lineage specification. In young guts, Sob restricts intestinal stem cell proliferation and promotes enteroendocrine differentiation while limiting excessive enterocyte differentiation. We have also found that the transcription factor Exex, the Notch pathway inhibitor Numb, and the enterocyte differentiation regulator Dawdle act downstream of Sob to regulate proliferation and differentiation. Our findings position Sob as a critical molecular switch linking stem cell dysfunction to gut ageing.