The chondrocranium in craniofacial development and disease

颅面发育和疾病中的软骨颅骨

• 批准号: 10327271
• 负责人: JOAN Therese RICHTSMEIER
• 金额: $ 49.08万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10327271
• 关键词: 3-Dimensional; Acids; Affect; Age; Anatomy; Apert-Crouzon syndrome; Apoptosis; Appearance; Awareness; Birth; Bone Resorption; Brain; Cartilage; Cell Lineage; Cell physiology; Cells; Cephalic; Chondrichthyes; Chondrocranium; Complex; Congenital Abnormality; Craniofacial Abnormalities; Craniosynostosis; Data; Dermal; Deterioration; Development; Discipline; Disease; Elements; Embryo; Embryonic Development; Embryonic Structures; Emotional; Ethnic group; Event; Face; Family; Functional disorder; Gene Expression; Goals; Graph; Growth; Image; Incidence; Individual; Investigation; Knowledge; Laboratories; Laboratory mice; Live Birth; Maintenance; Modernization; Morphology; Mus; Mutation; Nature; Operative Surgical Procedures; Osteoblasts; Pathway interactions; Patients; Phenotype; Play; Population; Preventive therapy; Procedures; Process; Production; Protocols documentation; Regulation; Reproducibility; Research; Research Design; Role; Sense Organs; Signal Transduction; Site; Skeletal system; Skeleton; Staging System; Stains; Surgical sutures; System; Techniques; Technology; Testing; Textbooks; Time; Tissues; Transgenic Mice; Vertebrates; base; bone; cleft lip and palate; coronal suture; craniofacial; craniofacial development; cranium; deep learning; design; fibroblast growth factor receptor 2c; histological specimens; imaging Segmentation; in silico; innovation; microCT; molecular marker; mouse model; novel; novel therapeutics; osteogenic; premature; reconstruction; scaffold; sex; spatiotemporal; three-dimensional modeling; tool

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.

大多数颅缝早闭症的研究都集中在皮颅上，皮颅是形成的第二个颅骨 在胚胎发育过程中，包括颅顶和面部骨骼的真皮骨。一个完全 一个独立的颅骨，软骨颅，在皮颅之前发育，以支持胚胎的生长。 大脑和其他感觉器官。从历史上看，软骨颅已经在脊椎动物中进行了研究， 被认为是颅面发育的基础，但颅面生物学家并不熟知， 至今还没有在实验室老鼠身上进行过研究。软骨颅由软骨形成， 虽然部分软骨内骨化，但其他部分在胚胎15-16天左右开始退化， 鼠标通过仔细分析整个安装和组织学标本，我们已经记录了 选择的软骨颅元素的同步退化， 特别是生长中的皮颅的皮骨。这些观察结果表明， 协调，局部扩张（真皮骨）和吸收（软骨）的机制， 在发育和进化上独立的骨骼系统。我们的项目，由强大的初步支持 小鼠软骨颅的数据，旨在检验一个中心假设：软骨颅服务于 作为结构和功能的支架，用于以后的皮颅成分的发育，包括 颅穹隆缝的形成。基于不同细胞之间的边界 种群通常作为组织组织者，我们认识到建立和维持稳定的 限制不同细胞群混合的边界对正常发育至关重要，并提出了一种 研究设计，询问软骨颅/皮颅边界对协调 头骨的发育。我们将询问特定部位的细胞，以确定其功能过程， 保持界限。然后使用Fgfr 2c +/C342 Y小鼠颅缝早闭模型，我们将研究 相关软骨颅/皮颅边界在两种颅缝早闭发展中的作用 表型：冠状缝过早闭合和面中部异常生长。的 软骨颅由不规则形状的软骨组成，其中许多是短暂的，需要我们 构思新的分析工具。我们将完成一个创新系统的开发， 在严格的时间控制下，从微型计算机断层扫描图像中通过计算机重建软骨颅骨， 在胚胎时期精确地描绘3D软骨颅解剖结构，并建立 软骨颅在皮颅的发育过程中。实现我们的目标将丰富教科书知识， 通过定义软骨颅在皮颅生成中的作用， 表型，提供有关无数颅面异常的病理生理学信息，并揭示 开发新疗法的潜在途径。

项目成果

Embryonic and early postnatal cranial bone volume and tissue mineral density values for C57BL/6J laboratory mice.

• DOI: 10.1002/dvdy.458
• 发表时间: 2022-07
• 期刊: Developmental dynamics : an official publication of the American Association of Anatomists

A dysmorphic mouse model reveals developmental interactions of chondrocranium and dermatocranium.

• DOI: 10.7554/elife.76653
• 发表时间: 2022-06-15
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Motch Perrine, Susan M.;Pitirri, M. Kathleen;Durham, Emily L.;Kawasaki, Mizuho;Zheng, Hao;Chen, Danny Z.;Kawasaki, Kazuhiko;Richtsmeier, Joan T.;Zhu, Min
• 通讯作者: Zhu, Min

It takes two: Building the vertebrate skull from chondrocranium and dermatocranium.

这需要两个步骤：用软骨颅骨和皮颅骨构建脊椎动物头骨。

• 发表时间: 2020
• 期刊: Vertebrate zoology
• 影响因子: 2.1
• 作者: Pitirri,MKathleen;Kawasaki,Kazuhiko;Richtsmeier,JoanT
• 通讯作者: Richtsmeier,JoanT

Differential Effects of the Fgfr2c C342Y Mutation on Developing Cranial Cartilage.

Fgfr2c C342Y 突变对发育中的颅软骨的不同影响。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Durham,EmilyL;Kawasaki,Mizuho;Pitirri,MK;Perrine,SusanMM;Kawasaki,Kazuhiko;Richtsmeier,JoanT
• 通讯作者: Richtsmeier,JoanT

Single-cell analysis identifies a key role for Hhip in murine coronal suture development.

• DOI: 10.1038/s41467-021-27402-5
• 发表时间: 2021-12-08
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Holmes G;Gonzalez-Reiche AS;Saturne M;Motch Perrine SM;Zhou X;Borges AC;Shewale B;Richtsmeier JT;Zhang B;van Bakel H;Jabs EW
• 通讯作者: Jabs EW