The chondrocranium in craniofacial development and disease

大多数关于颅缝融合的研究集中在第二个形成的颅骨--皮颅上 在胚胎发育过程中，它由颅顶的真皮骨骼和面部骨骼组成。一个完整的 独立的颅骨，即软骨颅骨，在皮颅之前发育，以支持胚胎。 大脑和其他感觉器官。从历史上看，脊椎动物对软骨颅骨进行了研究，并 被认为是颅面发育的基础，但它并不为颅面生物学家和 到目前为止还没有在实验室小鼠身上进行过研究。软骨头盖骨是由软骨和 虽然它的部分在软骨内骨化，但其他部分在胚胎15-16天左右开始退化 那只老鼠。通过对整架和组织标本的仔细分析，我们记录了 精选软骨颅骨软骨片的出现和叠加同步恶化 生长中的皮头骨的特殊真皮骨骼。这些观察到的信号表明 两者协调、局部扩张(真皮骨骼)和吸收(软骨)的机制 发育和进化上分离的骨骼系统。我们的项目，得到了强有力的初步支持 小鼠软骨颅骨的数据，旨在检验一个中心假设：软骨颅骨服务于 作为一种结构和功能支架，用于以后皮肤颅骨元素的开发，包括 颅穹隆缝合的形成。基于共同的发现，不同细胞之间的边界 人口经常充当组织者，我们认识到建立和维持稳定 限制不同细胞群体的混合对正常发育至关重要的边界，并提出了一种 询问软骨颅骨/皮肤颅骨边界对协调的重要意义的研究设计 头骨的发育。我们将询问特定地点的细胞以确定起作用的过程 保持边界。然后使用Fgfr2c/C342Y小鼠模型进行颅缝融合，我们将研究 相关的软骨-颅骨/皮肤-颅骨分界在两例颅缝融合的发生中的作用 表型：冠状缝过早闭合，面中部异常生长。那就是 软骨头骨是由不规则形状的软骨组成的，其中许多软骨的寿命很短，这要求我们 构思新的分析工具。我们将完成创新系统的开发，以解剖和 在严格的时间控制下，从微型计算机断层扫描图像重建硅胶中的软骨颅骨， 在3D中精确描绘胚胎时期的软骨颅骨解剖结构，并确定 软骨头骨在皮颅骨发育中的作用。实现我们的目标将丰富教科书上的知识 通过确定软骨头盖骨在皮肤颅骨生产中的作用来实现颅面发育 表型，提供与无数头面部异常的病理生理学有关的信息，并揭示 开发新疗法的潜在途径。

Most investigations of craniosynostosis focus on the dermatocranium, the second cranial skeleton to form during embryogenesis that comprises the dermal bones of the cranial vault and facial skeleton. A completely separate cranial skeleton, the chondrocranium, develops before the dermatocranium to support the embryonic brain and other sense organs. Historically, the chondrocranium has been studied across the vertebrates and is recognized as fundamental to craniofacial development, but it is not well known to craniofacial biologists and has never been studied in the laboratory mouse until now. The chondrocranium is formed of cartilage and though parts of it ossify endochondrally, other portions begin to degenerate by about embryonic day 15-16 in the mouse. By careful analysis of whole mount and histological specimens, we have documented the synchronized deterioration of select chondrocranial elements with the appearance and superimposition of particular dermal bones of the growing dermatocranium. These observations signal the existence of a mechanism for the coordinated, localized expansion (dermal bones) and resorption (cartilage) of two developmentally and evolutionarily separate skeletal systems. Our project, supported by strong preliminary data of the mouse chondrocranium, is designed to test a central hypothesis: that the chondrocranium serves as a structural and functional scaffold for the later development of dermatocranial elements including the formation of cranial vault sutures. Based on the common finding that boundaries between different cell populations often serve as tissue organizers, we recognize the establishment and maintenance of stable boundaries that restrict the mixing of different cell populations as critical to proper development, and propose a research design that interrogates the chondrocranial/dermatocranial boundary as significant to the coordinated development of the skull. We will interrogate cells at specific sites to determine the processes that function to maintain the boundaries. Then using the Fgfr2c+/C342Y mouse model for craniosynostosis, we will investigate relevant chondrocranial/dermatocranial boundaries operative in the development of two craniosynostosis phenotypes: premature closure of the coronal suture and abnormal growth of the midface. That the chondrocranium is composed of irregularly shaped cartilages, many of which are short-lived, requires that we conceive new tools for analysis. We will complete development of an innovative system to dissect and reconstruct the chondrocranium in silico from micro computed tomography images with tight temporal control, precisely delineate chondrocranial anatomy in 3D over embryonic time, and establish the role of the chondrocranium in development of the dermatocranium. Achieving our goals will enrich textbook knowledge of craniofacial development by defining the role of the chondrocranium in the production of dermatocranial phenotypes, provide information relative to the pathophysiology of countless craniofacial anomalies, and reveal potential avenues for the development of novel therapeutics.