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About the Authors:
Yen-Chi Wu
Affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States of America
Kyu-Sun Lee
Affiliations Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States of America, BioNanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
Yan Song
Affiliations Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States of America, School of Life Sciences and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
Stephan Gehrke
Affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States of America
Bingwei Lu
* E-mail: [email protected]
Affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States of America
ORCID http://orcid.org/0000-0002-5807-7014Abstract
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.
Author summary
Stem cells are functional units in the development, maintenance, and regeneration of tissues in multicellular organisms. Defects in stem cell regulation can compromise tissue homeostasis and result in proliferative or degenerative diseases. Our understanding of the molecular and cellular mechanisms regulating the in vivo behavior of stem cells is still incomplete. 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. Previous genetic studies have uncovered the evolutionarily conserved Numb-N signaling pathway that regulates...