title: Epidermal development, growth control, and homeostasis in the face of centrosome amplification.
abstract: As nucleators of the mitotic spindle and primary cilium, centrosomes play crucial roles in equal segregation of DNA content to daughter cells, coordination of growth and differentiation, and transduction of homeostatic cues. Whereas the majority of mammalian cells carry no more than two centrosomes per cell, exceptions to this rule apply in certain specialized tissues and in select disease states, including cancer. Centrosome amplification, or the condition of having more than two centrosomes per cell, has been suggested to contribute to instability of chromosomes, imbalance in asymmetric divisions, and reorganization of tissue architecture; however, the degree to which these conditions are a direct cause of or simply a consequence of human disease is poorly understood. Here we addressed this issue by generating a mouse model inducing centrosome amplification in a naturally proliferative epithelial tissue by elevating Polo-like kinase 4 (Plk4) expression in the skin epidermis. By altering centrosome numbers, we observed multiciliated cells, spindle orientation errors, and chromosome segregation defects within developing epidermis. None of these defects was sufficient to impart a proliferative advantage within the tissue, however. Rather, impaired mitoses led to p53-mediated cell death and contributed to defective growth and stratification. Despite these abnormalities, mice remained viable and healthy, although epidermal cells with centrosome amplification were still appreciable. Moreover, these abnormalities were insufficient to disrupt homeostasis and initiate or enhance tumorigenesis, underscoring the powerful surveillance mechanisms in the skin.
authors.affiliation: Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065;
authors.forename: Anita
authors.initials: A
authors.lastname: Kulukian
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Holland
authors.affiliation: CNRS UMR-5237, Centre de Recherche en Biochimie Macromoleculaire, University of Montpellier, Montpellier 34093, France;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vitre
authors.affiliation: Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065;
authors.forename: Shruti
authors.initials: S
authors.lastname: Naik
authors.affiliation: Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.affiliation: Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065 fuchslb@rockefeller.edu.
authors.forename: Elaine
authors.initials: E
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D060049:Asymmetric Cell Division / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D018385:Centrosome / Q000378:metabolism*; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; C088051:Plk4 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Plk4; centrosome amplification; epidermal development; mitosis