Defining the functional role of Bone Morphogenic Protein Signaling Pathway in the formation of the enteric nervous system

肠道神经系统(ENS)是人体肌壁内的固有神经系统。 整个胃肠道(GI)。ENS由一系列相互连接的肠神经节组成。 并负责调节蠕动、水分平衡和局部胃肠激素的调节 分泌物。虽然最近在理解ENS是如何产生的方面取得了许多进展 功能，但对其在早期胚胎发育过程中的形成知之甚少。在.期间 在发育过程中，有助于ENS的神经脊细胞(NCC)迁移到原始细胞中 前肠和尾部沿着肠道长度导航到其远端，在此期间它们 被称为肠神经脊细胞(ENCC)。ENCC未能完全填满肠道 并分化为神经元，导致ENS发育不正常，导致先天性 先天性巨结肠症，以肠神经节缺失为特征 GI的可变区。当ENCC沿着原始肠道迁移时，它们会收到不同的 来自周围肠道的外部信号--如GDNF、维甲酸和Sonic Hedgehog 组织和邻近的ENCC，促进其增殖、迁移、分化和 多功能性。事实上，尽管该领域已经表征了一些信号通路， ENCCs对肠道定植的重要性，基因调控和分子 将外在信号与ENCC迁移和神经元规范联系起来的机制很差 已澄清。 我使用斑马鱼胚胎的强大的基于活体成像和转录的初步数据 表明骨形态发生蛋白(BMP)信号通路高度富含 迁徙的ENCC，并需要以特定于时间的方式进行殖民和 沿肠道的神经元分化。斑马鱼胚胎提供了独特的机会 研究ENS因其透明、外在、快速发展而产生的发展。这 该方案验证了BMP信号通过以下方式直接调节肠道定植的假设 ENCC和它们的及时分化，以指示EN的建立。的具体目标 本研究的建议是：1.绘制BMP途径成员和BMP的时空表达图谱 斑马鱼胚胎发育过程中的途径活性，2.揭示斑马鱼胚胎发育的细胞机制 BMP信号控制ENCC肠道定植。这些实验的结果将阐明 驱动ENS发展和扩大基因调控网络的分子机制 这调节了神经脊细胞在胃肠道的定植。

The enteric nervous system (ENS) is the intrinsic nervous system within the muscle walls of the entire gastrointestinal (GI) tract. The ENS consists of a series of interconnected enteric ganglia and is responsible for mediating peristalsis, water balance, and regulation of local GI hormonal secretions. While much recent progress has been made in understanding how the ENS functions, far less is known about its formation during early embryological development. During development, neural crest cells (NCCs) that contribute to the ENS immigrate into the primitive foregut and navigate caudally along the gut length to its distal end, during which time they are referred to as enteric neural crest cells (ENCCs). A failure of ENCCs to fully populate the gut and differentiate into neurons leads to improper ENS development and results in the congenital disease, Hirschsprung Disease, which is characterized by a lack of enteric ganglia along variable regions of the GI. While ENCCs migrate along the primitive gut, they receive various extrinsic signals—such as GDNF, Retinoic Acid and Sonic Hedgehog—from the surrounding gut tissues and neighboring ENCCs that promotes their proliferation, migration, differentiation and multipotency. Indeed, while the field has characterized some of the signaling pathways that are important for colonization of the gut by the ENCCs, the gene regulatory and molecular mechanisms that link extrinsic signals to ENCC migration and neuronal specification is poorly elucidated. My strong in vivo imaging-based and transcriptomic preliminary data using zebrafish embryos indicates that the Bone Morphogenetic Protein (BMP) signaling pathway is highly enriched in migrating ENCCs and is required in a temporally-specific manner for their colonization and neuronal differentiation along the gut. Zebrafish embryos afford the unique opportunity to readily study development of the ENS due to their transparent, external, and rapid development. This proposal tests the hypothesis that BMP signaling directly regulates colonization of the gut by ENCCs and their timely differentiation to dictate the establishment of ENS. The specific aims of this proposal are 1. To map the spatiotemporal expression of BMP pathway members and BMP pathway activity in the developing zebrafish ENS, 2. Uncover the cellular mechanisms by which BMP signaling controls ENCC gut colonization. The results of these experiments will elucidate the molecular mechanism driving ENS development and expand the gene regulatory network that modulates the colonization of the GI tract by neural crest cells.