Evolution of embryonic polarity: The role of the Wnt signaling pathways

导致胚层起源的发育机制的演变是一个重要的未解决的问题。对这个问题的深入了解将来自于对古代动物（如刺胞动物）胚层分离的理解。PI一直在使用刺胞动物Nematostella vectensis，通过研究动物-植物（AV）轴的规格和进化来深入了解胚层进化，AV轴是大多数动物卵中发现的基本极性。发育信息不对称分布沿着这条轴是至关重要的胚层分离在许多物种，但其分子基础知之甚少。PI已经表明，在Nematostella中，胚层分离是由动物极源性卵裂球中进化上保守的Wnt/β-连环蛋白途径的选择性激活介导的。PI还表明，在未来的内胚层中典型Wnt信号传导的激活是由Dishevelled（Dsh）蛋白介导的，其定位于卵的动物极。在胚胎发生过程中，Dsh mRNA在全球范围内表达，但该蛋白质通过其在外胚层中的选择性去稳定化而在内胚层中富集。了解Dsh在Nematostella卵和胚胎中是如何调节的，可以深入了解导致AV轴和胚层进化的机制。本研究将利用功能分子生物学的方法，阐明1）限制Dsh对线虫内胚层细胞激活和稳定的分子机制; 2）确定Dsh是否在发育过程中调节肠道形态发生，以及3）确定斜视是否在脊椎动物中拮抗经典Wnt信号传导，并且定位于线虫卵中，具有将Dsh活性限制到内胚层的作用。总之，这些研究可能会为动物进化中最神秘的事件之一提供见解。拟议中的工作将涉及研究生和本科生的群体在科学代表性不足，这项研究的结果将纳入研究生和本科班教授的PI

The evolution of developmental mechanisms that led to the origin of germ layers is an important unsolved question. Insight into this question will come from understanding germ layer segregation in ancient animals such as cnidarians. The PI has been using the cnidarian Nematostella vectensis to gain insight into germ layer evolution by studying the specification and evolution of the animal-vegetal (AV) axis, a fundamental polarity found in most animal eggs. Developmental information asymmetrically distributed along this axis is crucial for germ layer segregation in many species, but its molecular basis is poorly understood. The PI has shown that in Nematostella, germ layer segregation is mediated by selective activation of the evolutionarily conserved Wnt/beta-catenin pathway in animal pole-derived blastomeres. The PI has also shown that the activation of canonical Wnt signaling in future endoderm is mediated by the Dishevelled (Dsh) protein, which is localized to the egg's animal pole. During embryogenesis Dsh mRNA is expressed globally but the protein is enriched in endoderm by its selective destabilization in ectoderm. Understanding how Dsh is regulated in Nematostella eggs and embryos may provide insight into mechanisms that led to evolution of the AV axis and the germ layers. In this research, the PI will use functional molecular approaches to elucidate 1) the molecular mechanisms that restrict Dsh activation and stability to endodermal cells in Nematostella; 2) determine if Dsh regulates gut morphogenesis during development and 3) determine if Strabismus, which has been shown to antagonize canonical Wnt signaling in vertebrates, and is localized in Nematostella eggs has a role in restricting Dsh activity to endoderm. Together, these studies are likely to provide insight into one of the most mysterious events in animal evolution. The proposed work will involve graduate and undergraduate students from groups under-represented in science, and results of this research will be incorporated into graduate and undergraduate classes taught by the PI