Multi-layered Control of the Exit from Stemness

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The mechanisms promoting the exit from stemness in normal neural stem cells likely can also drive brain tumor stem cells to differentiate. Thus, insights into control of the exit from stemness will improve our understanding of normal neurogenesis as well as brain tumor development. To exit from stemness, neural stem cell progeny must synchronously terminate self-renewal gene activity at the level of mRNAs and proteins. While tremandous progress has been made toward understanding the termination of self-renewal gene transcription during the exit from stemness, little is known about how post-transcriptional regulatory mechanisms terminate self-renewal gene activity. Importantly, nothing is known about how distinct control layers function synergistically to terminate self-renewal gene activity at all levels. By using the fly type II neural stem cell lineage as a paradigm, we demonstrated that transcriptional, translational and post-translational control function as part of an integrated gene regulation system that synchronously terminates self-renewal gene activity at all levels in the stem cell progeny. In this proposal, we focus on translational and post- translational control of self-renewal gene activity. We showed that RNA-binding protein complexes that are active in the stem cell progeny expedite self-renewal gene transcripts for decay by binding unique sequences in their 3'UTRs and recruiting multiple deadenylase concurrently. In addition, we showed that the combined effect of protein sequestration and proteolysis directed by multiple ubiquitin E3 ligase complexes rapidly and robustly terminates self-renewal protein activity. A robust transition from an “ON” to an “OFF” state is also required for precise spatiotemporal activity of many developmental signaling mechanisms that control patterning, proliferation and cell fate specification. Insights into our proposed integrated gene regulation system will be broadly applicable to the control of the exit from stemness in all stem cell lineages as well as the regulation of numerous cell fate decisions during normal development.