The origin and function of tendon progenitors in craniofacial morphogenesis and patterning

腱祖细胞在颅面形态发生和模式中的起源和功能

• 批准号: 8969380
• 负责人: JENNA L GALLOWAY
• 金额: $ 13.05万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8969380
• 关键词: Ablation; Address; Adult; Affect; Area; Behavior; Biological Assay; Biological Models; Biology; Birth; Bone Tissue; Branchial arch structure; Cell Communication; Cells; Cephalic; Characteristics; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Congenital Abnormality; Connective Tissue; Connective Tissue Cells; Development; Developmental Process; Differentiation and Growth; Disease; Dysmorphology; Engineering; Event; Face; Foundations; Future; Gene Expression; Genetic; Genome engineering; Growth; Growth and Development function; Human; Image; Knowledge; Life; Ligaments; Link; Maps; Modeling; Molecular; Morphogenesis; Morphology; Movement; Muscle; Musculoskeletal; Musculoskeletal Development; Musculoskeletal System; Neural Crest; Pathway interactions; Pattern; Population; Process; Regulation; Role; Site; Skeleton; Specific qualifier value; Staging; Structure; System; Temporomandibular Joint Disorders; Tendon structure; Tissues; Transgenic Organisms; Transplantation; Work; Zebrafish; base; bone; cell type; cellular imaging; craniofacial; craniofacial development; genome editing; insight; mutant; paracrine; postnatal; progenitor; public health relevance; research study; scleraxis; skeletal; tendon development

 DESCRIPTION (provided by applicant): The development of the craniofacial musculoskeletal system is a complex process involving the coordination of cell type specification, morphogenesis, patterning and growth. Many human craniofacial conditions such as congenital malformations or postnatal disorders often result from disruptions to one or many of these processes. Despite advances understanding the genetic basis of craniofacial diseases, many aspects of craniofacial development remain poorly understood. In particular, it is unknown how the connective tissue cell types, the tendons and ligaments, are specified and function in craniofacial musculoskeletal development and growth. Indeed, the precise placement and coordinated assembly of the musculoskeletal tissues is required for proper movement. Within the cranial skeleton, abnormal assembly or growth of the musculoskeletal system can result in craniofacial dysmorphology or disease. Tendons and ligaments are essential components of the musculoskeletal system by serving to connect the muscle and bone tissues. Surprisingly, given their importance in enabling movement, very little is known about their formation and function in regulating musculoskeletal patterning and growth. Transplantation studies have suggested that the neural crest derived connective tissues pattern the muscle attachment sites, but the specific function of the cranial tendon and ligament progenitors in this process or in the regulation of other events in craniofacial development has not been explored. We aim to address these major questions using the zebrafish model system. In the zebrafish, we have established that the tendons and ligaments in the craniofacial region are analogous to mammalian tendons in gene expression, morphology, developmental regulation, and ultrastructural characteristics. Using our tendon and ligament markers and a photoconvertible transgenic line, we will create a precise fate map of the tendon and ligament progenitors within the early pharyngeal arch domains. These lineage experiments will be the basis for future studies focusing on tendon cell specification and differentiation in different functional contexts. Next, we have engineered transgenic lines to perform tendon and ligament cell ablation experiments, thus determining their paracrine role in craniofacial development and growth. Finally, we have created scx mutant zebrafish lines to study its role in tendon elongation and craniofacial musculoskeletal morphogenesis. Together, these experiments provide an integral step towards elucidating the molecular pathways regulating tendon and ligament cell induction and function in the context of craniofacial musculoskeletal development, and have the potential to impact our understanding of craniofacial disorders.

 描述（由申请人提供）：颅面肌肉骨骼系统的发育是一个复杂的过程，涉及细胞类型规范、形态发生、模式化和生长的协调。许多人类颅面疾病，如先天性畸形或产后疾病，往往是由于中断一个或多个这些过程。尽管对颅面疾病的遗传基础的了解取得了进展，但颅面发育的许多方面仍然知之甚少。特别是，它是未知的结缔组织细胞类型，肌腱和韧带，是指定和功能在颅面肌肉骨骼发育和生长。事实上，肌肉骨骼组织的精确放置和协调组装是正确运动所必需的。在颅骨骨骼内，肌肉骨骼系统的异常组装或生长可导致颅面畸形或疾病。肌腱和韧带是肌肉骨骼系统的重要组成部分，用于连接肌肉和骨骼组织。令人惊讶的是，鉴于它们在使运动的重要性，很少有人知道它们的形成和功能，在调节肌肉骨骼模式和生长。移植研究表明，神经嵴衍生的结缔组织图案的肌肉附着点，但在这个过程中，或在颅面发育的其他事件的调节颅肌腱和韧带祖细胞的具体功能尚未探讨。我们的目标是使用斑马鱼模型系统来解决这些主要问题。在斑马鱼中，我们已经确定，在颅面区域的肌腱和韧带类似于哺乳动物肌腱的基因表达，形态，发育调节和超微结构特征。使用我们的肌腱和韧带标记和光转换转基因系，我们将创建一个精确的命运地图的肌腱和韧带祖细胞内的早期咽弓域。这些谱系实验将是未来研究肌腱细胞在不同功能背景下的特化和分化的基础。接下来，我们设计了转基因系来进行肌腱和韧带细胞消融实验，从而确定它们在颅面发育和生长中的旁分泌作用。最后，我们建立了scx突变的斑马鱼品系，以研究其在肌腱延长和颅面肌肉骨骼形态发生中的作用。总之，这些实验提供了一个完整的步骤，阐明调节肌腱和韧带细胞的诱导和功能的分子途径在颅面肌肉骨骼发育的背景下，并有可能影响我们对颅面疾病的理解。