Genetic mechanisms of craniofacial dermal development

描述（申请人提供）：皮肤由外层、表皮和真皮下层组成。真皮诱导并支持皮肤中的毛囊、腺体、神经和血管。患有局灶性皮肤发育不全、先天性皮肤发育不全、大伤口和严重烧伤的人缺乏正常的真皮和皮肤功能。尽管真皮的重要性，很少有人知道的胚胎起源和命运选择的真皮在不同部位的哺乳动物胚胎。真皮可以起源于体节、侧板中胚层和颅神经嵴。在本研究中，我们将重点研究颅面皮肤谱系中的出现机制和Wnt信号功能。随着最近出现的优雅的遗传工具，它现在才有可能结合联合收割机空间和时间的突变分析信号通路与细胞谱系研究，以确定如何诱导真皮细胞的身份和跟踪运动的真皮祖细胞在胚胎的背景下。我们已经确定了一个关键的作用β-连环蛋白，Wnt信号的中央转导，在颅面真皮在小鼠胚胎的发展。我们有独特的能力来实现这项建议的具体目标。在目标1中，我们将结合最近开发的遗传谱系标记工具来描述颅面皮肤谱系的出现。在Aim 2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性丧失和获得来定义颅面真皮谱系中Wnt信号传导功能的机制。在Aim 3中，我们检验了这样一个假设，即最早的真皮祖细胞标志物Dermol是Wnt信号传导促进真皮遗传程序的关键介质。这项研究的结果将首次全面了解颅面真皮在小鼠胚胎中的发育情况。识别促进各种祖细胞组织中真皮细胞命运的信号将使我们能够沿着真皮途径引导间充质干细胞分化，并制造能够诱导皮肤的毛发和腺体、加速伤口愈合和恢复功能性皮肤的真皮。对身体不同部位真皮诱导和发育的潜在机制的研究为理解先天性真皮缺陷、获得性皮肤损伤和正常皮肤图案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.