Cellular and Molecular Mechanisms of Patterned Growth of the Mammalian Skull

哺乳动物头骨模式生长的细胞和分子机制

• 批准号: 8048004
• 负责人: Robert E. Maxson
• 金额: $ 36.95万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048004
• 关键词: Address; Affect; Anterior; Apical; Bone Growth; Brain; Calvaria; Cells; Complex; Congenital Abnormality; Craniosynostosis; Cues; Defect; Development; Disease; Elements; Embryo; Enhancers; Event; Eye; Frontal bone structure; Functional disorder; Gene Dosage; Genes; Genetic; Growth; Head; Health; Human; Indium; Label; Lead; Learning; Location; Meninges; Mesenchymal; Mesenchyme; Mesoderm; Molecular; Morphogenesis; Mutation; Neural Crest; Osteogenesis; Parietal; Parietal bone structure; Pathway interactions; Pattern; Pattern Formation; Population; Population Control; Positioning Attribute; Process; Property; Relative (related person); Role; Shapes; Signal Transduction; Slice; Specific qualifier value; Staging; Structure; Testing; Tooth structure; Work; base; bone; cell motility; computerized data processing; coronal suture; cranium; in vivo; interest; life history; migration; migratory population; mind control; mutant; osteogenic; osteoprogenitor cell; precursor cell; prevent; progenitor; promoter; research study; response

DESCRIPTION (provided by applicant): This is a proposal to investigate the genetic control of patterned growth during the morphogenesis of a complex, multicomponent structure, the mammalian skull vault. More broadly, this proposal focuses on how interactions between distinct migratory mesenchymal cell populations regulate patterned growth. During skull vault development, cells derived from the neural crest and mesoderm migrate into positions above the eye, between the brain and a layer of non-osteogenic head mesoderm. There, in response to unknown cues they coalesce into the frontal and parietal bone rudiments and expand apically, ultimately coming into apposition with their paired counterparts. Although these events have been documented in broad outline, little is known about the developmental mechanisms that underlie them. Key issues that remain unresolved include whether cell migration has a role in rudiment elongation, how the pattern of the bones is determined, and what processes control the initial specification and differentiation of the frontal and parietal bone anlagen. Interactions between neural crest and mesoderm have long been postulated to be important in these processes, but how or even whether these interactions contribute to skull patterning remains unclear. Here we propose to address these questions. We have three Specific Aims: In the first, we will investigate the properties, cellular dynamics, and fate of a newly-defined population of migratory osteogenic precursor cells that contribute to the frontal and parietal bones. We will continue to carry out diI labeling experiments in conjunction with exo utero development of injected embryos to assess the fate and developmental function of migratory osteogenic precursor cells. We will evaluate a potential mechanism of frontal and parietal bone growth: that growth occurs by elongation of a rudiment of osteogenic cells through a preexisting layer of non- osteogenic mesenchyme. We will test the hypothesis that MOP cells originate in a population of noggin- expressing cells adjacent to the developing frontal and parietal bone rudiments In the second Specific Aim We will test the hypothesis that interactions between neural crest and mesoderm are essential for the growth of the calvarial rudiments and the anterior-posterior and dorso-ventral patterning of the frontal and parietal bones. We will continue to test the idea that Msx1/2 are required in the neural crest for the apical expansion of the frontal bone rudiment, and that changes in MOP cell life history contribute to dorso-ventral patterning defects of Msx mutants. We will also examine the mechanism by which the relative activity Msx2 in the neural crest and mesoderm controls the shape of the frontal and parietal bones, the location of the coronal suture, and thus patterning along the a/p axis. In the final Specific Aim, we will examine an interaction between FoxC1 and Msx1/2 that has revealed a signaling network by which the cell layers adjacent to the brain control the development of the frontal and parietal bone progenitor populations. This will entail a further characterization of FoxC1 mutants, as well as tests for a genetic interaction between Msx1/2 and FoxC1. We will also test of the hypothesis that FoxC1 interacts directly with a Bmp-responsive element in the Msx2 promoter, negatively regulating the response of Msx2 to Bmp signaling. The significance of the proposed work is that it addresses fundamental mechanisms of pattern formation as well as the pathophysiology of disorders affecting the growth and patterning of calvarial bones, including familial parietal foramina and craniosynostosis. PUBLIC HEALTH RELEVANCE: This is a proposal to study how the skull forms and how two genes-Msx2 and Msx2-control the shape of bones of the skull. Msx genes are of special interest because humans with mutations in MSX2 and MSX2 have birth defects that affect their skulls and teeth. By studying how these genes work, we will learn more about basic processes of skull development as well as how mutations in Msx1 and 2 lead to birth defects. In the long term, this work may help to devise new treatments of such birth defects.

描述（由申请人提供）：这是一项提议，旨在研究复杂，多组分结构的形态发生过程中对图案生长的遗传控制。从更广泛的角度来看，该提案重点是不同迁移间充质细胞种群之间的相互作用如何调节图案增长。在头骨穹顶发育过程中，源自神经rest和中胚层的细胞迁移到眼睛上方的位置，大脑和非稳态的中胚层之间的位置。在那里，为了回应未知的提示，他们将它们合并为额叶和顶骨基础上，并顶端扩展，最终与配对的对应物融为一体。尽管这些事件已被广泛概述，但对它们的发展机制知之甚少。尚未解决的关键问题包括细胞迁移是否在基础伸长，如何确定骨骼的模式以及哪些过程控制额叶和顶骨Anlagen的初始规范和分化。长期以来，神经rest和中胚层之间的相互作用在这些过程中很重要，但是这些相互作用是否有助于这些相互作用尚不清楚。在这里，我们建议解决这些问题。我们有三个特定的目标：首先，我们将研究新定义的迁移成骨前体细胞的特性，细胞动力学和命运，这些细胞有助于额叶和顶骨。我们将继续进行DII标记实验，并结合注射的胚胎的Exo子宫开发，以评估迁移成骨前体细胞的命运和发育​​功能。我们将评估额叶和顶骨生长的潜在机制：生长是通过通过非成骨性间质的先前存在的层延长成骨细胞的延伸而发生的。我们将检验以下假设：摩托艇细胞起源于第二个特定目的的Noggin-表达细胞群，与发展中的额叶和顶骨界限相邻，我们将检验以下假设：神经脆性和中胚层之间的相互作用对于钙质层次的层次和中层和前骨和偏向于偏向于偏向于钙质和偏向于ventriper和ventriper的生长至关重要。我们将继续测试以下观点：MSX1/2在神经rest中需要用于额骨骨骼基础的根尖膨胀，并且MOP细胞寿命的变化有助于MSX突变体的多索 - 腹膜模式缺陷。我们还将检查神经rest和中胚层中的相对活性MSX2的机制，控制额骨和顶骨的形状，冠状缝合线的位置，从而沿A/P轴模式。在最终的特定目的中，我们将研究FOXC1和MSX1/2之间的相互作用，该相互作用揭示了一个信号网络，通过该网络，与大脑相邻的细胞层控制额叶和顶骨祖细胞种群的发展。这将需要进一步表征FOXC1突变体，并测试MSX1/2和FOXC1之间的遗传相互作用。我们还将检验以下假设：FOXC1与MSX2启动子中BMP响应元件直接相互作用，从而负调节MSX2对BMP信号的响应。拟议工作的意义在于，它解决了模式形成的基本机制，以及影响钙化骨骼生长和模式的疾病的病理生理学，包括家族性顶叶孔孔和颅骨流症。公共卫生相关性：这是研究颅骨如何形成以及两个基因MSX2和MSX2-Control如何形成头骨骨骼形状的建议。 MSX基因具有特别的兴趣，因为MSX2和MSX2突变的人具有影响其头骨和牙齿的先天缺陷。通过研究这些基因的工作原理，我们将进一步了解颅骨发育的基本过程以及MSX1和2中的突变如何导致出生缺陷。从长远来看，这项工作可能有助于设计出对这种先天缺陷的新疗法。