title: The PDK1-Rsk Signaling Pathway Controls Langerhans Cell Proliferation and Patterning.
abstract: Langerhans cells (LC), the dendritic cells of the epidermis, are distributed in a distinctive regularly spaced array. In the mouse, the LC array is established in the first few days of life from proliferating local precursors, but the regulating signaling pathways are not fully understood. We found that mice lacking the kinase phosphoinositide-dependent kinase 1 selectively lack LC. Deletion of the phosphoinositide-dependent kinase 1 target kinases, ribosomal S6 kinase 1 (Rsk1) and Rsk2, produced a striking perturbation in the LC network: LC density was reduced 2-fold, but LC size was increased by the same magnitude. Reduced LC numbers in Rsk1/2(-/-) mice was not due to accelerated emigration from the skin but rather to reduced proliferation at least in adults. Rsk1/2 were required for normal LC patterning in neonates, but not when LC were ablated in adults and replaced by bone marrow-derived cells. Increased LC size was an intrinsic response to reduced LC numbers, reversible on LC emigration, and could be observed in wild type epidermis where LC size also correlated inversely with LC density. Our results identify a key signaling pathway needed to establish a normal LC network and suggest that LC might maintain epidermal surveillance by increasing their "footprint" when their numbers are limited.
authors.affiliation: Division of Cell Signaling and Immunology, College of Life Science, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors.forename: Rossana
authors.initials: R
authors.lastname: Zaru
authors.affiliation: Division of Cell Signaling and Immunology, College of Life Science, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Matthews
authors.affiliation: Division of Cell Signaling and Immunology, College of Life Science, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Edgar
authors.affiliation: Division of Cell Signaling and Immunology, College of Life Science, University of Dundee, Dundee DD1 5EH, United Kingdom;
authors.forename: Alan R
authors.initials: AR
authors.lastname: Prescott
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; and.
authors.forename: Diego
authors.initials: D
authors.lastname: Gomez-Nicola
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique Unite Mixté de Recherche 7104, INSERM U 964, University of Strasbourg, 67404 Illkirch, France.
authors.forename: André
authors.initials: A
authors.lastname: Hanauer
authors.affiliation: Division of Cell Signaling and Immunology, College of Life Science, University of Dundee, Dundee DD1 5EH, United Kingdom; c.watts@dundee.ac.uk.
authors.forename: Colin
authors.identifier: http://orcid.org/0000-0001-6183-2087
authors.initials: C
authors.lastname: Watts
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D002465:Cell Movement; D049109:Cell Proliferation; D048429:Cell Size; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D005434:Flow Cytometry; D007801:Langerhans Cells / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010766:Phosphorylation; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3