title: Essential Role of Polarity Protein Par3 for Epidermal Homeostasis through Regulation of Barrier Function, Keratinocyte Differentiation, and Stem Cell Maintenance.
abstract: Partitioning-defective (Par) proteins contribute to multiprotein complexes that drive cell polarity and fate in invertebrates. Of these, the ternary Par3-atypical protein kinase C-Par6 polarity complex mediates asymmetry in various systems, whereas Par3 and aPKC/Par6 can also act independently. aPKC-λ has recently been implicated in epidermal differentiation and stem cell fate; however, whether Par3 contributes to the homeostasis of adult stratified epithelia is currently unknown. Here, we provide functional evidence that epidermal Par3 loss disturbed the inside-out skin barrier, coinciding with altered expression and localization of principle tight junction components, and that epidermal differentiation and thickness were increased. Moreover, Par3 inactivation caused an initial expansion and later decline of hair follicle bulge stem cells, accompanied by an enrichment of committed progenitors, formation of hypertrophic sebaceous glands, and increased epidermal differentiation, suggesting aberrant cell fate decisions. Importantly, and opposite to aPKCλ deletion, Par3 loss did not enhance perpendicular cell divisions. Instead, in Par3-deficient hair follicles, spindles were shifted toward planar orientation, indicating that abnormal differentiation after Par3 inactivation is unlikely to be attributed to increased perpendicular spindle orientation. Collectively, mammalian Par3 controls the epidermal barrier, differentiation, and stem cell maintenance in the pilosebaceous unit, which are all essential for the homeostasis of an important barrier-forming epithelium.
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany.
authors.forename: Noelle J A
authors.initials: NJA
authors.lastname: Ali
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany.
authors.forename: Martim
authors.initials: M
authors.lastname: Dias Gomes
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany.
authors.forename: Ronja
authors.initials: R
authors.lastname: Bauer
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Brodesser
authors.affiliation: Center for Biochemistry, Medical Faculty, University of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
authors.forename: Catherin
authors.initials: C
authors.lastname: Niemann
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany. Electronic address: sandra.iden@uk-koeln.de.
authors.forename: Sandra
authors.initials: S
authors.lastname: Iden
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011493:Protein Kinase C / Q000378:metabolism*; D011897:Random Allocation; D012380:Role; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: C115015:PKC-3 protein; D011493:Protein Kinase C