Abstract
Notch (N) signaling is central to the self-renewal of neural stem cells (NSCs) and other tissue stem cells. Its deregulation compromises tissue homeostasis and contributes to tumorigenesis and other diseases. How N regulates stem cell behavior in health and disease is not well understood. Here we show that N regulates bantam (ban) microRNA to impact cell growth, a process key to NSC maintenance and particularly relied upon by tumor-forming cancer stem cells. Notch signaling directly regulates ban expression at the transcriptional level, and ban in turn feedback regulates N activity through negative regulation of the Notch inhibitor Numb. This feedback regulatory mechanism helps maintain the robustness of N signaling activity and NSC fate. Moreover, we show that a Numb-Myc axis mediates the effects of ban on nucleolar and cellular growth independently or downstream of N. Our results highlight intricate transcriptional as well as translational control mechanisms and feedback regulation in the N signaling network, with important implications for NSC biology and cancer biology.
Highlights
Balancing self-renewal with differentiation is a key property of all stem cells [1,2,3]
The Drosophila central nervous system neural stem cells called neuroblasts have offered an excellent model system for uncovering key mechanisms and player involved in stem cell regulation
In the type II NB lineages, which differs from type I NB lineages by possessing transit-amplifying intermediate progenitors (IPs) and are hierarchically similar to mammalian neural stem cells (NSCs), impaired N signaling leads to NB loss whereas N hyperactivation causes the dedifferentiation of IPs into cancer stem cell (CSC)-like tumorinitiating NBs [6,7,8]
Summary
Balancing self-renewal with differentiation is a key property of all stem cells [1,2,3]. Tipping such balance can have detrimental consequences, resulting in lineage depletion or tumorigenesis. N signaling is critically required for lineage homeostasis of both Drosophila and mammalian NSCs [3,4,5]. In the type II NB lineages, which differs from type I NB lineages by possessing transit-amplifying intermediate progenitors (IPs) and are hierarchically similar to mammalian NSCs, impaired N signaling leads to NB loss whereas N hyperactivation causes the dedifferentiation of IPs into cancer stem cell (CSC)-like tumorinitiating NBs [6,7,8]. Dedifferentiation has been recognized as a key mechanism in tumorigenesis in mammals, highlighting the relevance of Drosophila type II NBs to the understanding of human cancer biology
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