TGF BETA SIGNALING AND CRANIOFACIAL MORPHOGENESIS

TGF Beta 信号传导和颅面形态发生

• 批准号: 7035338
• 负责人: Yang Chai
• 金额: $ 35.79万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035338
• 关键词: biotechnology; cell differentiation; cell growth regulation; cell migration; cell proliferation; cleft palate; congenital oral /facial /cranial defect; dental development; disease /disorder model; embryonic stem cell; functional /structural genomics; gene deletion mutation; gene expression; gene targeting; genetic promoter element; genetic regulation; genetically modified animals; homeobox genes; laboratory mouse; mesenchyme; neural crest; phenotype; protein signal sequence; tissue /cell culture; transforming growth factors

DESCRIPTION (provided by applicant): Cleft palate represents one of the major groups of congenital birth defects in the human population. Despite recent advancements in medical intervention, babies born with cleft palate often suffer multiple handicaps that significantly compromise the quality of their lives. Cranial neural crest (CNC) is an important population of multipotent embryonic progenitor cells, which ultimately contribute to a diverse array of differentiated craniofacial tissues, including the palatal mesenchyme, and plays an integral role during palatogenesis. An understanding of the manner in which CNC cells contribute to palatal development and the molecular mechanism, which regulates the fate of CNC are critical for understanding normal craniofacial development as well as CNC-related congenital malformations. Multiple growth and transcription factors have been identified as critical regulators for palatogenesis. Specifically, TGF-beta plays a pivotal role in regulating the fate of medial edge epithelium during palatal fusion. It is not well understood, however, what is the functional significance of TGF-beta signaling in regulating the fate of CNC derived palatal mesenchyme. To address this issue, we have generated an animal model with conditional TGF-beta type II receptor (TGF-beta IIRfl/fl;Wnt1-Cre) gene ablation in neural crest cells. These TGF-beta IIRfl/fl;Wnt1-Cre mice show cleft palate and other craniofacial defects with 100 percent phenotype penetrance. Significantly, there is normal CNC migration into the first branchial arch of TGF-beta IIRfl/fl;Wnt1-Cre embryos, indicating that disruption of TGF-( signaling does not adversely affect CNC migration. Therefore, TGF-beta-mediated gene expression is specifically required locally during palatal development. Taking advantage of our TGF-beta IIRfl/fl;Wnt1-Cre and other mutant animal models we design studies to investigate the hierarchy of TGF-beta signaling in regulating the fate of CNC cells during palatogenesis by testing the hypothesis that TGF-beta signaling regulates the expression of homeobox gene Msx1, which in turn controls the progression of cell cycle to regulate the fate of CNC-derived palatal mesenchymal cells during palatogenesis. 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）：腭裂是人类先天性出生缺陷的主要群体之一。尽管医疗干预最近取得了进展，但出生时患有腭裂的婴儿经常遭受多种障碍，严重影响了他们的生活质量。颅神经嵴（CNC）是一个重要的多能胚胎祖细胞群，最终形成多种分化的颅面组织，包括腭间充质，并在腭发育过程中发挥着不可或缺的作用。了解 CNC 细胞促进腭发育的方式以及调节 CNC 命运的分子机制对于了解正常颅面发育以及与 CNC 相关的先天畸形至关重要。多种生长和转录因子已被确定为腭发育的关键调节因子。具体而言，TGF-β 在腭融合过程中调节内侧边缘上皮的命运中起着关键作用。然而，尚不清楚 TGF-β 信号传导在调节 CNC 衍生的腭间充质命运中的功能意义是什么。为了解决这个问题，我们在神经嵴细胞中建立了条件性 TGF-β II 型受体 (TGF-β IIRfl/fl;Wnt1-Cre) 基因消融的动物模型。这些 TGF-β IIRfl/fl;Wnt1-Cre 小鼠表现出腭裂和其他颅面缺陷，表型外显率达 100%。值得注意的是，CNC 正常迁移到 TGF-β IIRfl/fl;Wnt1-Cre 胚胎的第一鳃弓，表明 TGF-( 信号传导的破坏不会对 CNC 迁移产生不利影响。因此，TGF-β 介导的基因表达是利用我们的 TGF-β IIRfl/fl;Wnt1-Cre 和其他突变动物模型，我们设计了研究来研究 TGF-β 信号传导在调节 CNC 命运中的层次结构。通过测试 TGF-β 信号传导调节同源盒基因 Msx1 的表达这一假设，该基因反过来控制细胞周期的进展，从而调节腭发育过程中 CNC 衍生的腭间充质细胞的命运，最终，这项研究将提供一个关于腭发育期间细胞的研究。更好地了解 TGF-β 信号级联如何在正常颅面发育过程中调节 CNC 细胞的命运，以及信号传导破坏如何导致颅面畸形。