title: Laminin-511 is an epithelial message promoting dermal papilla development and function during early hair morphogenesis.
abstract: Hair morphogenesis takes place through reciprocal epithelial and mesenchymal signaling; however, the mechanisms controlling signal exchange are poorly understood. Laminins are extracellular proteins that play critical roles in adhesion and signaling. Here we demonstrate the mechanism of how laminin-511 controls hair morphogenesis. Dermal papilla (DP) from laminin-511 mutants showed developmental defects by E16.5, including a failure to maintain expression of the key morphogen noggin. This maintenance was critical as exogenous introduction of noggin or sonic hedgehog (Shh) produced downstream from noggin was sufficient to restore hair follicle development in lama5(-/-) (laminin-511-null) skin. Hair development required the beta1 integrin binding but not the heparin binding domain of laminin-511. Previous studies demonstrated that Shh signaling requires primary cilia, microtubule-based signaling organelles. Laminin-511 mutant DP showed decreased length and structure of primary cilia in vitro and in vivo. Laminin-511, but not laminin-111, restored primary cilia formation in lama5(-/-) mesenchyme and triggered noggin expression in an Shh- and PDGF-dependent manner. Inhibition of laminin-511 receptor beta1 integrin disrupted DP primary cilia formation as well as hair development. These studies show that epithelial-derived laminin-511 is a critical early signal that directs ciliary function and DP maintenance as a requirement for hair follicle downgrowth.
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.forename: Mindy C
authors.initials: MC
authors.lastname: DeRouen
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Nguyen
authors.forename: Ngon T
authors.initials: NT
authors.lastname: Nguyen
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ido
authors.forename: Kenji
authors.initials: K
authors.lastname: Harada
authors.forename: Kiyotoshi
authors.initials: K
authors.lastname: Sekiguchi
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Morgan
authors.forename: Jeffery H
authors.initials: JH
authors.lastname: Miner
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Oro
authors.forename: M Peter
authors.initials: MP
authors.lastname: Marinkovich
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000166:cytology / Q000378:metabolism; D002923:Cilia / Q000378:metabolism; D020405:Dermis / Q000166:cytology / Q000378:metabolism; D006197:Hair / Q000196:embryology* / Q000254:growth & development; D007150:Immunohistochemistry; D007797:Laminin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009024:Morphogenesis; D009154:Mutation; D017434:Protein Structure, Tertiary
chemical_list: D007797:Laminin; C531281:laminin-511, mouse