Role of BMP Antagonism in Craniofacial and Foregut Development

最近在发育生物学研究中的一个令人兴奋的发现是， 吻侧前肠内胚层（FGE）可导致直接肠上皮细胞的内源性和外源性畸形， 与人类重大出生缺陷的关系。前肠缺损的一个重要组成部分是气管食管 瘘，其中气管和食管未能从早期正确形成 内胚层管FGE也是调节颅面的关键信号的来源 例如，前肠信号缺陷可导致严重的下颌发育不全 （下颌发育不全）。尽管这些机制具有实际重要性， 控制前肠发育的这些内在和外在方面仍然是未知的。的 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， 小鼠胚胎的喙部组织。我们以前的工作表明，BMP拮抗剂的丢失 Noggin和Chordin导致气管食管瘘和下颌骨发育不全。这些 BMP拮抗剂在前原条中表达，这是FGE的来源。后来他们 在中轴线上，包括底板、脊索和背侧FGE。基于我们 目前的数据，我们的中心假设是，持续的轴向中线BMP拮抗作用是一个积极的， 前肠和颅面发育所必需的内胚层信号网络的调节器。 然而，也有证据与备择假设一致：在任何一种情况下， BMP拮抗作用的相关要求是在原肠形成期间和之后立即进行正常 早期前肠内胚层的形成，从而间接地为前肠的后续内在 和外在的发展角色。解决这些问题将提供关键的洞察力， BMP拮抗作用的基本作用和这些出生缺陷的一般机制。 因此，我们直接测试我们的中心假设和替代假设，通过以下方式 具体目标：1.确定需要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

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.