Laminin-511 is an epithelial message promoting dermal papilla development and function during early hair morphogenesis.
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.
Gao
Jing
J
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
DeRouen
Mindy C
MC
Chen
Chih-Hsin
CH
Nguyen
Michael
M
Nguyen
Ngon T
NT
Ido
Hiroyuki
H
Harada
Kenji
K
Sekiguchi
Kiyotoshi
K
Morgan
Bruce A
BA
Miner
Jeffery H
JH
Oro
Anthony E
AE
Marinkovich
M Peter
MP
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
D007797:Laminin; C531281:laminin-511, mouse