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 ␤1 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 ␤1 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.[Keywords: Laminin; primary cilium; basement membrane; integrin; hair] Supplemental material is available at http://www.genesdev.org.

Restoration of the intrinsic properties of human dermal papilla in vitro

“…However, considering that DP growth suppression due to BIO (Yamauchi and Kurosaka, 2009) represents a major drawback of DPAC, BIO may be substituted by recombinant WNT3A (Kishimoto et al, 2000;Shimizu and Morgan, 2004) to maintain the intrinsic properties and proliferative capacity of dpacDP cells. Because past reports suggested that activation of multiple biological pathways is necessary to fully maintain DP characteristics in vitro (Kishimoto et al, 2000;Shimizu and Morgan, 2004;Rendl et al, 2008), DPAC could be more potentiated by the addition of activators of other signaling pathways, including the Sonic hedgehog, Notch, and Endothelin pathways (Gao et al, 2008;Driskell et al, 2009;Hu et al, 2010). In contrast to DP cells, fibroblasts cultured in DPAC reduced ALP expression (data not shown).…”

Maintenance of Glomerular Filtration Barrier Integrity Requires Laminin α5

“…Furthermore, a recent report showed that laminin ␣5 in the hair follicle basement membrane is important for cilia structure and function. 31 However, here a direct effect of laminin ␣5 reduction on tubular epithelial cell behavior seems not to be the complete story; neither mode of glomerular rescue should affect the TBMs, yet cystogenesis was inhibited. There are no precedents for congenital nephrotic syndrome and/or hematuria causing early cystogenesis in humans or in mice.…”

Laminin β1a controls distinct steps during the establishment of digestive organ laterality

“…We identify a distinctive distribution of Lam1 that is associated with sites of cilia formation during KV morphogenesis. Interestingly, in mammals, Lam-511 regulates primary cilia formation during dermal papilla development (Gao et al, 2008), suggesting that the role of laminin in ciliogenesis may be conserved in different organs and across species. Yet the mechanism by which Lamb1a modulates cilia formation is not clear.…”