Role of BMP Antagonism in Craniofacial and Foregut Development

BMP 拮抗剂在颅面和前肠发育中的作用

• 批准号: 7934261
• 负责人: JOHN A KLINGENSMITH
• 金额: $ 8.74万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-08 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934261
• 关键词: Ablation; Address; Anterior; Cells; Congenital Abnormality; Data; Defect; Development; Developmental Biology; Dorsal; Embryo; Endoderm; Ensure; Esophageal; Esophagus; Fibroblast Growth Factor; Genes; Human; Jaw; Lead; Mandible; Mandibular Prominence; Mesoderm; Micrognathism; Mus; Neural Crest; Neural Crest Cell; Phenotype; Primitive Streaks; Primitive foregut structure; Process; Research; Resolution; Role; Signal Transduction; Source; Testing; Tissues; Trachea; Tracheoesophageal Fistula; Tube; Work; base; chordin; clinically significant; craniofacial; gastrulation; insight; malformation; mutant; notochord; paracrine; spatiotemporal

An exciting finding of recent research in developmental biology is that defective development of the rostral foregut endoderm (FGE) can result in both intrinsic and extrinsic malformations of direct relevance to major human birth defects. An important group of foregut defects is tracheoesophageal fistula, where the trachea and esophagus fail to be formed correctly from the early endodermal tube. The FGE is also the source of critical signals that regulate craniofacial development; for example, defective foregut signaling can lead to severe mandibular hypoplasia (underdevelopment of the lower jaw). Despite their pragmatic importance, the mechanisms controlling these intrinsic and extrinsic aspects of foregut development remain largely unknown. The long-term objective of our work is to understand how intercellular signaling directs the development of rostral tissues in the mouse embryo. Our previous work showed that loss of the BMP antagonists Noggin and Chordin results in both tracheo-esophageal fistula and mandibular hypoplasia. These BMP antagonists are expressed in the anterior primitive streak, the source of the FGE. Later, they are expressed in the axial midline, including floorplate, notochord and dorsal FGE. Based on our current data, our central hypothesis is that ongoing axial midline BMP antagonism is an active regulator of an endodermal signaling network essential for foregut and craniofacial development. However, there is also evidence consistent with the alternative hypothesis: That in either case the relevant requirement for BMP antagonism is during and immediately after gastrulation for normal formation of the early foregut endoderm, and thus indirectly for the foregut's subsequent intrinsic and extrinsic developmental roles. Resolving these questions will provide key insight into the essential roles of BMP antagonism and the mechanisms of these birth defects in general. Accordingly, we directly test both our central and alternative hypotheses, by means of the following specific aims: 1. Determine the tissues in which BMP antagonist expression is required for formation of the trachea and esophagus; 2. Determine the spatiotemporal requirement for Noggin and Chordin in mandibular outgrowth; and 3. Determine the interactions of BMP antagonism with the foregut endodermal signaling network.

发育生物学最新研究的一个令人兴奋的发现是，发育缺陷 头侧前肠内胚层（FGE）可导致直接内胚层的内在和外在畸形 与人类主要出生缺陷的相关性。一组重要的前肠缺陷是气管食管缺陷 瘘管，气管和食管从早期就未能正确形成 内胚层管。 FGE 也是调节颅面的关键信号的来源 发展;例如，前肠信号传导缺陷可能导致严重的下颌发育不全 （下颌发育不全）。尽管这些机制具有务实的重要性， 控制前肠发育的这些内在和外在方面仍然很大程度上未知。这 我们工作的长期目标是了解细胞间信号传导如何指导发育 小鼠胚胎中的吻部组织。我们之前的工作表明 BMP 拮抗剂的丢失 Noggin 和 Chordin 会导致气管食管瘘和下颌发育不全。这些 BMP 拮抗剂在前原条中表达，即 FGE 的来源。后来，他们 表达于轴向中线，包括底板、脊索和背侧 FGE。基于我们的 根据目前的数据，我们的中心假设是，持续的轴中线 BMP 拮抗作用是一种主动的 对前肠和颅面发育至关重要的内胚层信号网络的调节者。 然而，也有证据与替代假设相一致：无论哪种情况 正常情况下，BMP 拮抗作用的相关要求是在原肠胚形成期间和之后立即 早期前肠内胚层的形成，从而间接影响前肠随后的内在 和外在的发展角色。解决这些问题将为我们提供重要的见解 BMP 拮抗作用的重要作用以及这些出生缺陷的一般机制。 因此，我们通过以下方式直接测试我们的中心假设和替代假设 具体目标： 1. 确定 BMP 拮抗剂表达所需的组织 气管和食道； 2.确定Noggin和Chordin的时空要求 下颌骨生长； 3. 确定 BMP 拮抗作用与前肠的相互作用 内胚层信号网络。