Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development.
Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development.
复制标题
DOI：
10.1371/journal.pgen.1006151
复制
发表时间：
2016-07
期刊：
影响因子：
4.5
通讯作者：
Ezhkova E
中科院分区：
文献类型：
--
作者：
Perdigoto CN;Dauber KL;Bar C;Tsai PC;Valdes VJ;Cohen I;Santoriello FJ;Zhao D;Zheng D;Hsu YC;Ezhkova E
越来越多的证据表明，发育程序受到信号通路以及转录和表观遗传过程之间复杂相互作用的严格调控。在这里，我们已经发现了转录和形态线索之间的协调，以指定默克尔细胞，知之甚少的皮肤细胞，介导光触摸感觉。在鼠背部皮肤中，默克尔细胞是触觉圆顶的一部分，触觉圆顶是由特化角质形成细胞、默克尔细胞和传入神经元组成的皮肤结构，并且仅位于初级毛囊周围。我们发现，发展中的初级毛囊功能作为一个小生境所需的默克尔细胞规格。我们发现，表皮内的声刺猬（Shh）信号，在发展中的毛囊中的Shh配体的生产启动，需要默克尔细胞规格。Shh对默克尔细胞形成的重要性进一步得到了胚胎表皮祖细胞中Shh过表达导致异位默克尔细胞的事实的加强。有趣的是，Shh信号在初级毛囊、次级毛囊和三级毛囊中是共同的，这提高了存在限制性机制的可能性，该机制仅在初级毛囊周围调节默克尔细胞特化。事实上，我们发现表皮中Polycomb抑制复合物2（PRC2）的缺失导致与所有毛发类型相关的异位默克尔细胞的形成。我们发现，PRC2的损失扩大了领域的表皮细胞主管分化成默克尔细胞通过上调关键的默克尔分化基因，这是已知的PRC2的目标。重要的是，PRC2介导的默克尔细胞分化程序的抑制需要诱导性Shh信号传导以形成成熟的默克尔细胞。我们的研究阐明了表观遗传和形态原之间的相互作用如何调节哺乳动物皮肤结构的复杂图案和形成。默克尔细胞是受神经支配的触觉感受器细胞，负责轻微触觉。它们起源于胚胎表皮干细胞，在皮肤的多毛区域，组织成触觉圆顶。触摸圆顶是高度图案化的结构，仅在初级毛囊周围形成。引人注目的是，控制默克尔细胞形成的机制在很大程度上是未知的。在这里，我们表明，毛囊功能作为一个小生境所需的默克尔细胞的形成。我们发现，表皮内的声波刺猬（Shh）信号，启动生产的Shh在发展中的毛囊，需要默克尔细胞规格，而Shh在胚胎表皮祖细胞过度表达导致异位默克尔细胞。有趣的是，Shh信号在所有类型的毛发中都是共同的，这表明存在限制性机制，允许默克尔细胞特异性仅发生在初级毛发周围。事实上，我们发现表皮中Polycomb抑制复合物2（PRC2）的缺失导致所有毛发类型周围异位默克尔细胞的形成。我们表明，PRC2的损失扩大了领域的表皮细胞主管分化成默克尔细胞通过关键的默克尔分化基因的去抑制，但是，诱导Shh信号仍然需要成熟的默克尔细胞的形成。我们的研究阐明了表观遗传和形态发生因子之间的相互作用如何建立哺乳动物皮肤的复杂图案和形成。
An increasing amount of evidence indicates that developmental programs are tightly regulated by the complex interplay between signaling pathways, as well as transcriptional and epigenetic processes. Here, we have uncovered coordination between transcriptional and morphogen cues to specify Merkel cells, poorly understood skin cells that mediate light touch sensations. In murine dorsal skin, Merkel cells are part of touch domes, which are skin structures consisting of specialized keratinocytes, Merkel cells, and afferent neurons, and are located exclusively around primary hair follicles. We show that the developing primary hair follicle functions as a niche required for Merkel cell specification. We find that intraepidermal Sonic hedgehog (Shh) signaling, initiated by the production of Shh ligand in the developing hair follicles, is required for Merkel cell specification. The importance of Shh for Merkel cell formation is further reinforced by the fact that Shh overexpression in embryonic epidermal progenitors leads to ectopic Merkel cells. Interestingly, Shh signaling is common to primary, secondary, and tertiary hair follicles, raising the possibility that there are restrictive mechanisms that regulate Merkel cell specification exclusively around primary hair follicles. Indeed, we find that loss of Polycomb repressive complex 2 (PRC2) in the epidermis results in the formation of ectopic Merkel cells that are associated with all hair types. We show that PRC2 loss expands the field of epidermal cells competent to differentiate into Merkel cells through the upregulation of key Merkel-differentiation genes, which are known PRC2 targets. Importantly, PRC2-mediated repression of the Merkel cell differentiation program requires inductive Shh signaling to form mature Merkel cells. Our study exemplifies how the interplay between epigenetic and morphogen cues regulates the complex patterning and formation of the mammalian skin structures. Merkel cells are innervated touch-receptor cells that are responsible for light touch sensations. They originate from embryonic epidermal stem cells and, in hairy regions of skin, are organized in touch domes. Touch domes are highly patterned structures that form exclusively around primary hair follicles. Strikingly, the mechanisms controlling Merkel cell formation are largely unknown. Here, we show that the hair follicle functions as a niche required for Merkel cell formation. We find that intraepidermal Sonic hedgehog (Shh) signaling, initiated by the production of Shh in the developing hair follicles, is required for Merkel cell specification, whereas Shh overexpression in embryonic epidermal progenitors leads to ectopic Merkel cells. Interestingly, Shh signaling is common to all hair types, suggesting that there are restrictive mechanisms that allow Merkel cell specification to occur exclusively around primary hairs. Indeed, we find that loss of Polycomb repressive complex 2 (PRC2) in the epidermis leads to the formation of ectopic Merkel cells around all hair types. We show that PRC2 loss expands the field of epidermal cells competent to differentiate into Merkel cells through derepression of key Merkel-differentiation genes; however, inductive Shh signaling is still required for the formation of mature Merkel cells. Our study illustrates how the interplay between epigenetic and morphogen cues functions to establish the complex patterning and formation of the mammalian skin.