title: A Presenilin-2-ARF4 trafficking axis modulates Notch signaling during epidermal differentiation.
abstract: How primary cilia impact epidermal growth and differentiation during embryogenesis is poorly understood. Here, we show that during skin development, Notch signaling occurs within the ciliated, differentiating cells of the first few suprabasal epidermal layers. Moreover, both Notch signaling and cilia disappear in the upper layers, where key ciliary proteins distribute to cell-cell borders. Extending this correlation, we find that Presenilin-2 localizes to basal bodies/cilia through a conserved VxPx motif. When this motif is mutated, a GFP-tagged Presenilin-2 still localizes to intercellular borders, but basal body localization is lost. Notably, in contrast to wild type, this mutant fails to rescue epidermal differentiation defects seen upon Psen1 and 2 knockdown. Screening components implicated in ciliary targeting and polarized exocytosis, we provide evidence that the small GTPase ARF4 is required for Presenilin basal body localization, Notch signaling, and subsequent epidermal differentiation. Collectively, our findings raise the possibility that ARF4-dependent polarized exocytosis acts through the basal body-ciliary complex to spatially regulate Notch signaling during epidermal differentiation.
authors.affiliation: Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065.
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Ezratty
authors.affiliation: Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065.
authors.forename: H Amalia
authors.initials: HA
authors.lastname: Pasolli
authors.affiliation: Howard Hughes Medical Institute, Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065 fuchslb@rockefeller.edu.
authors.forename: Elaine
authors.initials: E
authors.lastname: Fuchs
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D064652:Basal Bodies / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism / Q000648:ultrastructure; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology / Q000378:metabolism / Q000648:ultrastructure; D017930:Genes, Reporter; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D038081:Organogenesis; D053764:Presenilin-1 / Q000378:metabolism; D053766:Presenilin-2 / Q000737:chemistry / Q000378:metabolism*; D021381:Protein Transport; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C560093:Arl13b protein, mouse; D053764:Presenilin-1; D053766:Presenilin-2; D051880:Receptors, Notch; D020727:ADP-Ribosylation Factors; C571368:ARF4 protein, mouse