Genetic mechanisms of craniofacial dermal development

颅面真皮发育的遗传机制

• 批准号: 8113280
• 负责人: RADHIKA P ATIT
• 金额: $ 33.02万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113280
• 关键词: Address; Adult; Aplasia Cutis Congenita; Biological Models; Blood Vessels; Body part; Burn injury; Cell Lineage; Cells; Cephalic; Chick Embryo; Chronic; Defect; Dehydration; Dermal; Dermis; Development; Dimensions; Dorsal; Embryo; Engineering; Epidermis; Focal Dermal Hypoplasia; Gene Targeting; Genetic; Genetic Programming; Gland; Goals; Hair; Hair follicle structure; Head; Infection; Knowledge; Lateral; Maps; Mediating; Mediator of activation protein; Mesenchymal Stem Cells; Mesoderm; Modeling; Molecular; Movement; Mus; Mutant Strains Mice; Nerve; Neural Crest; Neural Crest Cell; Outcome Study; Pathway interactions; Pattern; Phenotype; Research Personnel; Resolution; Role; Signal Pathway; Signal Transduction; Site; Skin; Skin Substitutes; Somites; Testing; Therapeutic; Tissue Engineering; Tissues; Transducers; Work; Wound Healing; appendage; beta catenin; craniofacial; fetal; hindbrain; in vivo; migration; mutant; progenitor; programs; stem cell differentiation; tool; transcription factor

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.

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。患有局灶性真皮发育不全、先天性皮肤发育不良、大伤口和严重烧伤的人缺乏正常的真皮和皮肤功能。尽管真皮很重要，但人们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嵴。在本提案中，我们将重点关注颅面真皮谱系中的出现机制和 Wnt 信号传导功能。随着最近出现的优雅遗传工具，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相结合，以确定如何诱导真皮细胞身份并跟踪胚胎背景下真皮祖细胞的运动。我们已经确定了β-连环蛋白（Wnt 信号传导的中心转导器）在小鼠胚胎颅面真皮发育中的关键作用。我们以独特的方式来解决该提案的具体目标。在 Aim1 中，我们将结合最近开发的遗传谱系标记工具来描述颅面真皮谱系的出现。在 Aim2 中，我们将通过分析 β-catenin 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 信号传导功能的机制。在 Aim3 中，我们测试了以下假设：Dermol（最早的真皮祖细胞标记）是 Wnt 信号传导在促进真皮遗传程序中的关键介质。这项研究的结果将首次全面了解小鼠胚胎中颅面真皮的发育情况。识别促进各种祖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了解先天性真皮缺陷、后天性皮肤损伤和正常皮肤图案提供了一个极好的模型。