Role of BMP Antagonism in Craniofacial and Foregut Development

发育生物学最新研究的一个令人兴奋的发现是，大脑发育有缺陷 吻部前部内胚层(FGE)可导致直肠癌的内源性和外源性畸形。 与人类重大先天缺陷的相关性。一组重要的前肠缺陷是气管-食道 瘘管，气管和食道不能从早期正确形成 内皮管。FGE也是调节颅面部的关键信号的来源 发育；例如，前庭信号缺陷可导致严重的下颌发育不全 (下颌骨发育不良)。尽管它们具有务实的重要性，但这些机制 控制前肠发育的这些内在和外在方面在很大程度上仍然是未知的。这个 我们工作的长期目标是了解细胞间信号如何引导发育 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骨发育不全。这些 BMP拮抗剂在FGE的来源--前原始纹路中表达。后来，他们 表达于中轴线，包括底板、脊索和背侧FGE。基于我们的 目前的数据，我们的中心假设是，正在进行的中轴线BMP拮抗是一种活跃的 对前肠和颅面发育至关重要的内胚层信号网络的调节器。 然而，也有证据与另一种假设相一致：无论是哪种情况， BMP拮抗的相关要求是在原肠形成过程中和之后立即正常 早期前肠内胚层的形成，从而间接地为前肠随后的内在 和外在的发育作用。解决这些问题将为我们提供对 BMP拮抗的基本作用和这些出生缺陷的一般机制。 因此，我们通过以下方法直接测试我们的中心假设和备选假设 具体目标：1.确定形成BMP拮抗剂所需的组织 气管和食道；2.确定Noggin和Chordin的时空要求 在下颌骨生长中的作用；以及3.确定BMP拮抗与前庭的相互作用 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.