Genetic mechanisms of craniofacial dermal development

描述（由申请人提供）：皮肤由外层、表皮和真皮层下层组成。真皮层诱导并支持皮肤中的毛囊、腺体、神经和血管。局灶性皮肤发育不全、先天性皮肤发育不全、大面积伤口和严重烧伤的人缺乏正常的真皮和皮肤功能。尽管真皮层非常重要，但对于哺乳动物胚胎不同部位的真皮层的胚胎起源和命运选择知之甚少。真皮可起源于体层、侧板中胚层和颅神经嵴。在本研究中，我们将重点关注Wnt在颅面真皮谱系中的出现机制和信号功能。随着最近优雅的遗传工具的出现，现在才有可能将信号通路的空间和时间突变分析与细胞谱系研究结合起来，以确定真皮细胞身份是如何诱导的，并在胚胎的背景下跟踪真皮祖细胞的运动。我们已经确定了-连环蛋白，Wnt信号传导的中心传感器，在小鼠胚胎颅面真皮发育中的关键作用。我们有独特的条件来处理这项建议的具体目标。在Aim1中，我们将结合最近开发的遗传谱系标记工具来描述颅面真皮谱系的出现。在ai2中，我们将通过分析β -连环蛋白功能突变体的组织特异性条件损失和获得来定义颅面真皮谱系中Wnt信号功能的机制。在Aim3中，我们验证了Dermol这个最早的真皮祖标记是Wnt信号在促进真皮遗传程序中的关键中介的假设。这项研究的结果将首次提供关于小鼠胚胎颅面真皮如何发育的全面观点。识别各种祖组织中促进真皮细胞命运的信号，将使我们能够引导间充质干细胞沿着真皮途径分化，制造出能够诱导皮肤毛发和腺体、加速伤口愈合和恢复皮肤功能的真皮层。对身体不同部位皮肤诱导和发育的潜在机制的研究为理解先天性皮肤缺陷、获得性皮肤损伤和正常皮肤模式提供了一个很好的模型。

DESCRIPTION (provided by applicant): The skin consists of the outer layer, epidermis and the underlying layer of the dermis. The dermis induces and supports the hair follicles, glands, nerves, and blood vessels in the skin. People with Focal Dermal Hypoplasia, Aplasia Cutis Congenita, large wounds, and severe burns lack normal dermis and skin function. Despite the importance of the dermis, very little is known about the embryonic origins and fate selection of dermis in different parts of the mammalian embryo. The dermis can originate from the somites, lateral plate mesoderm, and the cranial neural crest. In this proposal, we will focus on the mechanisms of emergence and Wnt signaling function in craniofacial dermal lineage. With the recent advent of elegant genetic tools, it is only now possible to combine spatial and temporal mutational analysis of signaling pathways with cell lineage studies to determine how the dermal cell identity is induced and track the movements of dermal progenitors in the context of the embryo. We have identified a critical role for beta-catenin, the central transducer of Wnt signaling, in the development of craniofacial dermis in the mouse embryo. We are uniquely poised to address the specific aims of this proposal. In Aim1, we will characterize the emergence of the craniofacial dermal lineage with a combination of recently developed genetic lineage marking tools. In Aim2, we will define the mechanism of Wnt signaling function in craniofacial dermal lineage by analyzing tissue-specific conditional loss and gain of beta-catenin function mutants. In Aim3, we test the hypothesis that Dermol, the earliest dermal progenitor marker, is the critical mediator of Wnt signaling in promoting the dermal genetic program. The results from this study will provide the first comprehensive view of how the craniofacial dermis develops in the mouse embryo. Identifying the signal that promotes dermal cell fate in various progenitor tissues will enable us to guide mesenchymal stem cell differentiation along the dermal pathway and manufacture dermis that is capable of inducing hair and glands of the skin, accelerating wound healing, and restoring functional skin. The study of underlying mechanisms of dermal induction and development in different parts of the body offers an excellent model for understanding congenital dermal defects, acquired skin damage, and normal skin patterning.