title: Botch promotes neurogenesis by antagonizing Notch.
abstract: Regulation of self-renewal and differentiation of neural stem cells is still poorly understood. Here we investigate the role of a developmentally expressed protein, Botch, which blocks Notch, in neocortical development. Downregulation of Botch in vivo leads to cellular retention in the ventricular and subventricular zones, whereas overexpression of Botch drives neural stem cells into the intermediate zone and cortical plate. In vitro neurosphere and differentiation assays indicate that Botch regulates neurogenesis by promoting neuronal differentiation. Botch prevents cell surface presentation of Notch by inhibiting the S1 furin-like cleavage of Notch, maintaining Notch in the immature full-length form. Understanding the function of Botch expands our knowledge regarding both the regulation of Notch signaling and the complex signaling mediating neuronal development.
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Zhikai
authors.initials: Z
authors.lastname: Chi
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zhang
authors.forename: Akinori
authors.initials: A
authors.lastname: Tokunaga
authors.forename: Maged M
authors.initials: MM
authors.lastname: Harraz
authors.forename: Sean T
authors.initials: ST
authors.lastname: Byrne
authors.forename: Andrew
authors.initials: A
authors.lastname: Dolinko
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Seth
authors.initials: S
authors.lastname: Blackshaw
authors.forename: Nicholas
authors.initials: N
authors.lastname: Gaiano
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D005722:gamma-Glutamylcyclotransferase
chemical_list: D002352:Carrier Proteins; C572776:GGCT protein, human; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D051880:Receptors, Notch; D005722:gamma-Glutamylcyclotransferase