TWISTED GASTRULATION AND MANDIBULAR ARCH MORPHOGENESIS

扭曲的原肠胚形成和下颌骨形态发生

• 批准号: 7194587
• 负责人: Anna Petryk
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7194587
• 关键词: TWISTED; GASTRULATION; MANDIBULAR; ARCH; MORPHOGENESIS

DESCRIPTION (provided by applicant): A significant number of human craniofacial syndromes are the result of abnormal development of the first (mandibular) branchial arch (BA1). Most of BA1 mesenchyme is derived from cephalic neural crest cells (NCC) that emerge from the lateral edges of the neural folds, migrate ventrally in close proximity to the developing pharynx, and populate BA1 primordia. At the level of BA1, NCCs receive signals from the local environment that regulate their proliferation, survival, and differentiation. Multiple developmental pathways are involved in regulating morphogenesis of BA1, with bone morphogenetic proteins (BMPs) playing a prominent role. Twsg1 is a secreted protein that binds to BMPs and modulates their activities. We have shown that Twsg1-deficient mice have abnormal morphogenesis of BA1, manifesting as agnathia, with variable degrees of accompanying craniofacial defects. Twsg1 mutant mice also show defects in foregut endoderm suggesting that Twsg1 signaling is necessary for foregut development. Our long-range goal is to understand molecular mechanisms underlying human craniofacial syndromes. The objective of the present study is to characterize the role of Twsg1 in mandibular arch morphogenesis. Our central hypothesis is that Twsg1 is required for morphogenesis of the medial region of BA1 and that foregut endoderm deficiency in Twsg1-/- mice affects patterning of cephalic NCC. The rationale for the proposed research is that knowledge obtained from this study will promote our understanding of the molecular and cellular basis of BA1 patterning that can ultimately lead to better diagnosis of human craniofacial syndromes, which result from abnormal development of BA1. Our studies will also inform how precise regulation of BMP signaling affects complex patterning events, such as those required for mandibular development. The following specific aims will be pursued: 1) Examine cephalic NCC formation and migration and mandibular arch morphogenesis in Twsg1-/- mice by using NCC- and BA1-specific markers, as well as assays of proliferation and apoptosis; 2) Identify genes regulated by Twsg1 signaling in BA1 development by using microarray technology; 3) Identify the cells that are the primary target of Twsg1 gene action in patterning of BA1 by generating endoderm-specific deletion of Twsg1; 4) Understand how excess of Twsg1 affects molecular boundaries of BMP signaling during BA1 morphogenesis by implanting Twsg1-soaked beads into mouse mandibular explants. Lay summary: Abnormal development of the lower jaw is a common finding in children with various craniofacial syndromes. We have identified a gene, Twsg1, that is important for jaw development in mice. Since Twsg1 gene is also present in humans and lower jaw development is similar in mice and humans, this work can lead to better understanding and ultimately diagnosis of human craniofacial syndromes.

描述(由申请人提供)：相当多的人类颅面综合征是第一(下颌)颧弓(BA1)异常发育的结果。大部分BA1间充质细胞是从神经褶的侧缘长出的头神经脊细胞(NCC)衍生而来，向腹侧靠近发育中的咽部迁移，并填充BA1原基。在BA1水平上，NCC接受来自当地环境的信号，这些信号调节它们的增殖、存活和分化。多种发育途径参与调控BA1的形态发生，其中骨形态发生蛋白(BMPs)起着重要作用。Twsg1是一种分泌蛋白，可与BMP结合并调节其活性。我们发现Twsg1基因缺陷小鼠存在BA1的形态发生异常，表现为嗅觉不全，并伴有不同程度的头面部缺陷。Twsg1突变小鼠也显示出前肠内胚层的缺陷，这表明Twsg1信号对前肠发育是必要的。我们的长期目标是了解人类颅面综合征的分子机制。本研究的目的是研究Twsg1在下颌弓形态发生中的作用。我们的中心假设是Twsg1是BA1内侧区域形态发生所必需的，Twsg1-/-小鼠的前肠内胚层缺陷影响头部NCC的图案化。拟议研究的基本原理是，从这项研究中获得的知识将促进我们对BA1模式的分子和细胞基础的理解，最终可以导致更好地诊断由BA1异常发育引起的人类颅面综合征。我们的研究还将揭示BMP信号的精确调控如何影响复杂的图案事件，如下颌发育所需的事件。本研究的具体目标如下：1)通过使用NCC和BA1特异的标记物以及增殖和凋亡的分析，检测Twsg1-/-小鼠头部NCC的形成、迁移和下颌骨弓的形态发生；2)利用基因芯片技术找出BA1发育中受Twsg1信号调控的基因；3)通过产生内胚层特异性的Twsg1缺失，确定Twsg1基因在BA1图案形成中的主要靶点；4)通过将Twsg1浸泡的珠子植入小鼠下颌骨外植体，了解过量的Twsg1如何影响BA1形态发生过程中BMP信号的分子边界。 摘要：下颌骨发育异常是各种颅面综合征儿童的常见表现。我们已经确定了一个基因Twsg1，它对小鼠的颌骨发育很重要。由于Twsg1基因也存在于人类中，而且小鼠和人类的下颌发育相似，这项工作可以导致对人类颅面综合征的更好理解和最终诊断。