Genetic mechanisms of craniofacial dermal development

描述(申请人提供)：皮肤由真皮的外层、表皮和底层组成。真皮诱导和支持皮肤中的毛囊、腺体、神经和血管。患有局限性皮肤发育不全、先天性皮肤再生不全、大面积创面和严重烧伤的人缺乏正常的真皮和皮肤功能。尽管真皮很重要，但对哺乳动物胚胎不同部位真皮的胚胎起源和命运选择知之甚少。真皮可起源于体节、侧板中胚层和颅神经脊。在这项研究中，我们将重点研究颅面部真皮细胞系中的突起机制和Wnt信号的功能。随着最近先进的遗传工具的出现，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，并跟踪真皮祖细胞在胚胎背景下的运动。我们已经确定了Wnt信号的中心转导因子β-catenin在小鼠胚胎头面部真皮发育中的关键作用。我们正独一无二地准备解决这项提案的具体目标。在Aim1中，我们将结合最近开发的遗传谱系标记工具来表征头面部真皮谱系的出现。在AIM2中，我们将通过分析组织特异性条件缺失和β-连环蛋白功能突变体的获得来确定Wnt信号在头面部皮肤谱系中的作用机制。在Aim3中，我们验证了一种假设，即作为最早的真皮祖细胞标记物，Derol是Wnt信号在促进真皮遗传程序中的关键中介。这项研究的结果将提供第一个全面的观点，如何在小鼠胚胎的颅面真皮发育。识别促进不同祖细胞组织中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，并制造能够诱导皮肤毛发和腺体、加速伤口愈合和恢复功能皮肤的真皮。对人体不同部位真皮诱导和发育的潜在机制的研究为了解先天性皮肤缺陷、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.