Abstract
The switch between quiescence and proliferation is central for neurogenesis and its alteration is linked to neurodevelopmental disorders such as microcephaly. However, intrinsic mechanisms that reactivate Drosophila larval neural stem cells (NSCs) to exit from quiescence are not well established. Here we show that the spindle matrix complex containing Chromator (Chro) functions as a key intrinsic regulator of NSC reactivation downstream of extrinsic insulin/insulin-like growth factor signalling. Chro also prevents NSCs from re-entering quiescence at later stages. NSC-specific in vivo profiling has identified many downstream targets of Chro, including a temporal transcription factor Grainy head (Grh) and a neural stem cell quiescence-inducing factor Prospero (Pros). We show that spindle matrix proteins promote the expression of Grh and repress that of Pros in NSCs to govern their reactivation. Our data demonstrate that nuclear Chro critically regulates gene expression in NSCs at the transition from quiescence to proliferation.
Highlights
The switch between quiescence and proliferation is central for neurogenesis and its alteration is linked to neurodevelopmental disorders such as microcephaly
We demonstrated that the spindle matrix complex represented by Chro functions downstream of InR/PI3K/TOR signalling pathway and regulates the expression of a temporal transcription factor Grainy head (Grh) and a quiescence-inducing transcription factor Pros to permit neural stem cells (NSCs) reactivation (Fig. 5)
This provides a previously missing link between extrinsic relay of signalling from blood-brain-barrier glia and subsequent activation of InR/PI3K/ TOR signalling in NSCs to intrinsic transcription factors Grh and Pros that regulate reactivation or quiescence of NSCs
Summary
The switch between quiescence and proliferation is central for neurogenesis and its alteration is linked to neurodevelopmental disorders such as microcephaly. NSC-specific in vivo profiling has identified many downstream targets of Chro, including a temporal transcription factor Grainy head (Grh) and a neural stem cell quiescence-inducing factor Prospero (Pros). In the mammalian adult brain, the majority of NSCs are in a mitotic inactive, quiescent state[1] They can exit quiescence and resume proliferation in response to extrinsic stimuli[2]. In Drosophila, spindle matrix proteins contain at least four nuclear proteins—Chromator/Chriz (Chro), Megator (Mtor), Skeletor and enhanced adult sensory threshold (East)[20,21,22] These spindle matrix proteins have intriguing cell cycle-dependent subcellular localization: they are localized to nucleus during interphase, and translocate to the mitotic spindle during mitosis[23]. Our study demonstrates a critical cell-intrinsic mechanism by which Chro functions as a critical nuclear factor to control gene expression during NSC reactivation
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