Regulation of Self-renewal and Differentiation in Adult Stem Cell Lineages: Lessons from the Drosophila Male Germ Line

Abstract

The ability to identify stem cells and trace their descendants in vivo has yielded insights into how self-renewal, proliferation, and differentiation are regulated in adult stem cell lineages. Analysis of male germ-line stem cells in Drosophila has revealed the importance of local signals from the microenvironment, the stem cell niche, in controlling stem cell behavior. Germ-line stem cells physically attach to the niche via localized adherens junctions that provide a polarity cue for orientation of centrosomes in interphase and the spindle in mitosis. As a result, stem cells divide asymmetrically: One daughter inherits attachment to the niche and remains within its embrace, whereas the other is displaced away and initiates differentiation. Strikingly, much as leukemia inhibitory factor (LIF) and transforming growth factor-β (TGF-β) signaling maintain mouse embryonic stem (ES) cells, maintenance of stem cell state in the Drosophila male germ line is regulated by cytokine-like signals from hub cells that activate the transcription factor STAT (signal transducer and activator of transcription) and TGF-β class signals from surrounding support cells that repress expression of a key differentiation factor. Surprisingly, transit-amplifying cells can revert to the stem cell state if they reoccupy the niche. Upon cessation of mitosis and the switch to terminal differentiation, germ cells express cell-type- and stage-specific transcription machinery components that drive expression of terminal differentiation genes, in part by removing Polycomb transcriptional silencing machinery.