title: Autophagy regulates Notch degradation and modulates stem cell development and neurogenesis.
abstract: Autophagy is a conserved, intracellular, lysosomal degradation pathway. While mechanistic aspects of this pathway are increasingly well defined, it remains unclear how autophagy modulation impacts normal physiology. It is, however, becoming clear that autophagy may play a key role in regulating developmental pathways. Here we describe for the first time how autophagy impacts stem cell differentiation by degrading Notch1. We define a novel route whereby this plasma membrane-resident receptor is degraded by autophagy, via uptake into ATG16L1-positive autophagosome-precursor vesicles. We extend our findings using a physiologically relevant mouse model with a hypomorphic mutation in Atg16L1, a crucial autophagy gene, which shows developmental retention of early-stage cells in various tissues where the differentiation of stem cells is retarded and thus reveal how modest changes in autophagy can impact stem cell fate. This may have relevance for diverse disease conditions, like Alzheimer's Disease or Crohn's Disease, associated with altered autophagy.
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge CB2 0XY, UK.|Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Angeleen
authors.initials: A
authors.lastname: Fleming
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ricketts
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Mariana
authors.initials: M
authors.lastname: Pavel
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Herbert
authors.initials: H
authors.lastname: Virgin
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Menzies
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D011992:Endosomes / Q000378:metabolism; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics*; D051881:Receptor, Notch1 / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: C518959:ATG16L1 protein, human; C532820:Atg16l1 protein, mouse; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1
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