Molecular Regulatory Mechanism of Calvarial Morphogenesis

颅骨形态发生的分子调控机制

• 批准号: 6954417
• 负责人: Yang Chai
• 金额: $ 35.47万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6954417
• 关键词: cell growth regulation; congenital oral /facial /cranial defect; craniofacial; developmental genetics; genetically modified animals; histogenesis; laboratory mouse; mammalian embryology; mesenchyme; neural crest; transforming growth factors

DESCRIPTION (provided by applicant): Calvaria malformations represent one of the major groups of congenital birth defects in the human population. Despite recent advancements in medical intervention, babies born with calvarial defects often suffer multiple handicaps that significantly compromise the quality of their lives. The cranial neural crest (CMC) is an important population of multipotent embryonic progenitor cells which ultimately contribute to a diverse array of differentiated craniofacial tissues, including the calvarial mesenchyme, and plays an integral role during calvarial morphogenesis. An understanding of the manner in which CMC cells contribute to calvaria development and the molecular mechanism which regulates the fate of CNC are critical for understanding normal craniofacial development as well as CMC-related congenital malformations. Multiple growth and transcription factors have been identified as critical regulators for calvarial morphogenesis. Specifically, TGF-beta in the CMC-derived mesenchyme can induce premature cranial suture obliteration in postnatal calvaria development. It is not understood; however, what is the functional significance of TGF-b signaling in regulating the fate of the CMC-derived mesenchyme during initial calvaria morphogenesis. To address this issue, we have generated mice with conditional Tgfbr2 fl/fl; Wnt1-Cre gene ablation in neural crest cells. These Tgfbr2 fl/fl; mice show missing frontal bones and other craniofacial malformations with 100% phenotype penetrance. Significantly, disruption of the TGF-b signaling does not adversely affect the CNC migration, indicating that the TGF-b-mediated gene expression is specifically required locally during calvarial morphogenesis. Taking advantage of our Tgfbr2 fl/fl and other mutant animal models we design studies to investigate the hierarchy of TGF-b signaling in regulating the fate of CNC cells during frontal bone development by testing the hypothesis that TGF-beta signaling regulates the expression of Msx1, which in turn controls the progression of cell cycle to regulate the fate of CMC-derived mesenchymal cells during frontal bone morphogenesis. Ultimately, this study will provide a better understanding on how the TGF- beta signaling cascade regulates the fate of CNC cells during normal craniofacial development and how signaling disruption can lead to craniofacial malformations.

描述（由申请人提供）：瓦尔瓦里亚畸形是人口中先天性先天缺陷的主要群体之一。尽管医疗干预的最新进展，但患有颅骨缺陷的婴儿通常会遭受多种障碍，从而严重损害了生活质量。颅神经rest（CMC）是多能胚胎祖细胞的重要种群，最终有助于包括钙化间质在内的各种分化的颅面组织，并在钙质形成过程中起着不可或缺的作用。对CMC细胞有助于钙调节发育的方式以及调节CNC命运的分子机制的理解对于理解正常的颅面发育以及与CMC相关的先天性畸形至关重要。多重生长和转录因子已被确定为钙化形态发生的关键调节剂。具体而言，CMC衍生的间充质中的TGF-beta可以在产后瓦尔瓦里亚发育中诱导过早的颅骨缝合剂。它不理解；然而，在初始钙质形态发生过程中，TGF-B信号传导在调节CMC衍生的间质的命运方面的功能意义是什么？为了解决这个问题，我们已经产生了有条件的TGFBR2 FL/FL的小鼠；神经rest细胞中的Wnt1-Cre基因消融。这些TGFBR2 fl/fl;小鼠表现出缺失的额骨和其他颅面畸形，具有100％的表型渗透率。值得注意的是，TGF-B信号传导的破坏不会对CNC迁移产生不利影响，这表明在钙化形态发生期间，在本地需要特异性TGF-B介导的基因表达。利用我们的TGFBR2 FL/FL和其他突变动物模型，我们设计研究来研究TGF-B信号传导在额骨发育过程中调节CNC细胞命运的层次结构，通过测试TGF-BETA信号传导调节MSX1的表达的假说这反过来控制了细胞周期的进展，以调节额骨形态发生过程中CMC衍生的间充质细胞的命运。最终，这项研究将更好地了解TGF-Beta信号传导如何调节正常颅面发育过程中CNC细胞的命运以及信号传导如何导致颅面畸形。