title: Numb is required for the production of terminal asymmetric cell divisions in the developing mouse retina.
abstract: In the developing nervous system, cell diversification depends on the ability of neural progenitor cells to divide asymmetrically to generate daughter cells that acquire different identities. While much work has recently focused on the mechanisms controlling self-renewing asymmetric divisions producing a differentiating daughter and a progenitor, little is known about mechanisms regulating how distinct differentiating cell types are produced at terminal divisions. Here we study the role of the endocytic adaptor protein Numb in the developing mouse retina. Using clonal numb inactivation in retinal progenitor cells (RPCs), we show that Numb is required for normal cell-cycle progression at early stages, but is dispensable for the production of self-renewing asymmetric cell divisions. At late stages, however, Numb is no longer required for cell-cycle progression, but is critical for the production of terminal asymmetric cell divisions. In the absence of Numb, asymmetric terminal divisions that generate a photoreceptor and a non-photoreceptor cell are decreased in favor of symmetric terminal divisions generating two photoreceptors. Using live imaging in retinal explants, we show that a Numb fusion protein is asymmetrically inherited by the daughter cells of some late RPC divisions. Together with our finding that Numb antagonizes Notch signaling in late-stage RPCs, and that blocking Notch signaling in late RPCs almost completely abolishes the generation of terminal asymmetric divisions, these results suggest a model in which asymmetric inheritance of Numb in sister cells of terminal divisions might create unequal Notch activity, which in turn drives the production of terminal asymmetric divisions.
authors.affiliation: Cellular Neurobiology Research Unit, Institut de recherches cliniques de Montréal (IRCM), H2W 1R7, QC, Canada.|Department of Anatomy and Cell Biology, McGill University, Montreal, H3A 2B2, QC, Canada.
authors.forename: Amel
authors.initials: A
authors.lastname: Kechad
authors.affiliation: Cellular Neurobiology Research Unit, Institut de recherches cliniques de Montréal (IRCM), H2W 1R7, QC, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Jolicoeur
authors.affiliation: Cellular Neurobiology Research Unit, Institut de recherches cliniques de Montréal (IRCM), H2W 1R7, QC, Canada.
authors.forename: Adele
authors.initials: A
authors.lastname: Tufford
authors.affiliation: Cellular Neurobiology Research Unit, Institut de recherches cliniques de Montréal (IRCM), H2W 1R7, QC, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Mattar
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, CB2 3DY, Cambridge, UK.
authors.forename: Renee W Y
authors.initials: RWY
authors.lastname: Chow
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, CB2 3DY, Cambridge, UK.
authors.forename: William A
authors.initials: WA
authors.lastname: Harris
authors.affiliation: Cellular Neurobiology Research Unit, Institut de recherches cliniques de Montréal (IRCM), H2W 1R7, QC, Canada.|Department of Anatomy and Cell Biology, McGill University, Montreal, H3A 2B2, QC, Canada.|Département de Médecine, Université de Montréal, H3T 1P1, QC, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Cayouette
mesh_terms: D000818:Animals; D060049:Asymmetric Cell Division / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C106293:Numb protein, mouse; D051880:Receptors, Notch