Laminin-511 is an epithelial message promoting dermal papilla development and function during early hair morphogenesis
Laminin-511 is an epithelial message promoting dermal papilla development and function during early hair morphogenesis
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DOI：
10.1101/gad.1689908
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发表时间：
2008-08-01
影响因子：
10.5
通讯作者：
Marinkovich, M. Peter
中科院分区：
文献类型：
--
作者：
Gao, Jing;DeRouen, Mindy C.;Marinkovich, M. Peter
毛发的形态发生是通过上皮细胞和间充质细胞之间相互的信号传导来实现的，然而，控制信号交换的机制却知之甚少。层粘连蛋白是在粘附和信号传导中起关键作用的细胞外蛋白。在这里，我们展示了层粘连蛋白-511如何控制毛发形态发生的机制。层粘连蛋白-511突变体的毛乳头（DP）在E16.5时表现出发育缺陷，包括未能维持关键形态原头蛋白的表达。这种维持是至关重要的，因为外源性引入头蛋白或从头蛋白下游产生的音刺猬（Shh）足以恢复lama 5（-/-）（层粘连蛋白-511-null）皮肤中的毛囊发育。毛发发育需要β 1整合素结合，但不需要层粘连蛋白-511的肝素结合域。以前的研究表明，Shh信号需要初级纤毛，微管为基础的信号细胞器。层粘连蛋白-511突变体DP在体外和体内显示初级纤毛的长度和结构减少。层粘连蛋白-511，而不是层粘连蛋白-111，恢复lama 5（-/-）间充质中的初级纤毛形成，并以Shh和PDGF依赖的方式触发头蛋白表达。层粘连蛋白-511受体β 1整合素的抑制破坏DP初级纤毛形成以及毛发发育。这些研究表明，上皮源性层粘连蛋白-511是一个关键的早期信号，指导纤毛功能和DP维持作为毛囊向下生长的要求。
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 beta 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 beta 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.