Fueling left-right asymmetry: the role of glycolysis in stomach curvature

项目摘要 左-右(LR)大小、形状和/或解剖位置的差异几乎存在于每个器官系统中。 因此，异常的LR不对称(称为异位排列，HTX)通常会导致多发性的、危及生命的 涉及复杂畸形和器官间不协调偏侧的出生缺陷。而早些时候 建立全球LR不对称性的胚胎事件已经得到了很好的研究，它是后期的器官- 对正常解剖至关重要的特定LR不对称形态发生事件；然而，对于大多数器官来说， 形成它们各自的LR不对称性的分子和细胞过程尚未阐明。这 应用程序将探索LR在糖酵解中不对称的新的和令人惊讶的概念- 分解葡萄糖生成三磷酸腺苷的原始代谢途径--参与了 器官形态发生不对称。已发表的研究表明，胃的向左弯曲，一个 在脊椎动物中保守的典型的LR不对称，取决于LR的不对称重排 间充质细胞转化为上皮(间充质向上皮转变；MET)，导致变薄和 左侧胃壁扩张。最近的左对右转录组图谱随后显示 胃弯曲时，胃左侧的糖酵解酶表达上调。作为糖酵解(AS 与线粒体呼吸相反)已知在其他情况下促进上皮-间充质可塑性， 这一意想不到的发现提出了一种有趣的可能性，即LR不对称糖酵解可能有助于LR 驱动曲率形态发生的不对称MET。在拟议的项目中，这一想法将严格 通过利用两个不同的两栖动物胚胎的独特属性进行测试，执行代谢组学，质量 光谱成像、糖酵解通量分析、药理扰动和左对右靶向试验 基因功能方面，确定糖酵解基因的功能(目标1)和糖酵解代谢基因(目标2) 胃曲形态发生。因此，R21的成功完成将证实这一耐人寻味的 假设器官偏侧性是由糖酵解中的LR不对称形成的，因此异常代谢 国家可能会助长与偏侧有关的出生缺陷的发展。

Project Summary Left-right (LR) differences in size, shape and/or anatomical position exist in almost every organ system. Consequently, abnormal LR asymmetry (known as heterotaxy, HTX) often leads to multiple, life threatening birth defects involving complex malformations and discordant laterality between organs. While the early embryonic events that establish global LR asymmetry have been well studied, it is the later-stage, organ- specific LR asymmetric morphogenesis events that are critical for normal anatomy; yet, for most organs, the molecular and cellular processes that sculpt their individual LR asymmetries have not been elucidated. This application will explore the novel and surprising concept that LR asymmetries in GLYCOLYSIS—the primordial metabolic pathway that breaks down glucose to generate ATP—are integrally involved in asymmetric organ morphogenesis. Published work has shown that leftward curvature of the stomach, an archetypical LR asymmetry conserved among vertebrates, depends on LR asymmetric rearrangements of mesenchymal cells into an epithelium (mesenchymal-to-epithelial transition; MET), causing thinning and expansion of the left stomach wall. Recent left vs right transcriptome profiling subsequently revealed that glycolysis enzymes are upregulated in the left side of the stomach during curvature. As glycolysis (as opposed to mitochondrial respiration) is known to promote epithelial-mesenchymal plasticity in other contexts, this unexpected finding raises the intriguing possibility that LR asymmetric glycolysis may facilitate the LR asymmetric MET that drives curvature morphogenesis. In the proposed project, this idea will be rigorously tested by exploiting the unique attributes of two different amphibian embryos, executing metabolomics, mass spectrometry imaging, glycolytic flux analyses, pharmacological perturbations, and left- vs right-targeted tests of gene function, to determine the function of glycolysis genes (Aim 1), and glycolytic metabolism (Aim 2) in stomach curvature morphogenesis. Successful completion of this R21 will therefore substantiate the intriguing premise that organ laterality is shaped by LR asymmetries in glycolysis, such that aberrant metabolic states may contribute to the development of laterality-related birth defects.