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.

最近在发育生物学方面的研究的一个令人兴奋的发现是 to骨内胚层（FGE）可以导致直接的内在和外在畸形 与主要的人类先天缺陷有关。重要的前肢缺陷是气管食管 瘘管，气管和食道无法从早期正确形成 内皮管。 FGE也是调节颅面的关键信号的来源 发展;例如，前述信号有缺陷会导致严重的下颌骨发育不全 （下颌的欠发达）。尽管具有务实的重要性，但机制还是 控制了前述发展的这些内在和外在方面，这在很大程度上是未知的。这 我们工作的长期目标是了解细胞间信号如何指导发展 小鼠胚胎中的鼻组织。我们以前的工作表明，BMP拮抗剂的丧失 Noggin和Chordin会导致气管食道瘘和下颌骨发育不全。这些 BMP拮抗剂在前原始条纹（FGE的来源）中表达。后来，他们 以轴向中线表示，包括地板，脊索和背部FGE。基于我们 当前数据，我们的中心假设是持续的轴向中线BMP拮抗是一种活跃的 内胚层信号网络的调节器，对于前肢和颅面发育至关重要。 但是，也有证据与替代假设一致的证据：在任何一种情况下 BMP拮抗作用的相关要求是胃胃肠道的正常要求 早期内胚层的形成，因此间接地是因为前身的固有 和外部发育作用。解决这些问题将为您提供关键的见解 BMP拮抗作用的基本作用和这些先天缺陷的机制。 因此，我们通过以下方式直接测试中央和替代假设 具体目的：1。确定形成需要BMP拮抗剂表达的组织 气管和食道； 2。确定Noggin和Chordin的时空要求 下颌生长；和3。确定BMP拮抗与前肢的相互作用 内胚层信号网络。