Localized determinants in vertebrate axis formation

描述(申请人提供)：人类的先天缺陷和癌症通常是由Wnt信号通路的错误调节引起的。在早期脊椎动物胚胎中，体轴的发育关键需要激活胚胎一侧的Wnt通路。在非洲爪蛙中，作为轴形成的主要模式生物，不对称的Wnt信号是通过储存在卵子中的母源分子的差异定位来实现的。这些决定因素通过受精后卵子皮质基于微管的旋转运动向未来的背侧转移。对这一过程的干扰导致胚胎缺乏背部组织。调节皮质旋转中的不对称性和轴形成中的Wnt激活的确切机制尚不清楚。来自母体功能丧失研究的数据，包括对这一提议的初步研究，已经涉及到植物局部因素。这项研究的长期目标是了解这些本地化的 胚轴形成中的母体基因产物。对这一提议的初步研究已经确定了母体Wnt信号在调节皮质旋转方面的潜力。还采用了在活体皮质旋转过程中监测微管动力学的新方法。这项建议的目的是确定植物微管阵列形成的潜在机制，并表征阵列上携带的潜在决定因素。其具体目的是确定定位的mRNAs在皮质旋转过程中控制微管组装的作用，确定这一过程在多大程度上受到卵母细胞中正在进行的Wnt信号的调控，并表征植物皮质中的蛋白质决定因素。

DESCRIPTION (provided by applicant): Human birth defects and cancers are often caused by misregulation of the Wnt signaling pathway. In early vertebrate embryos, development of the body axis critically requires the activation of the Wnt pathway on one side of the embryo. In the frog Xenopus, a predominant model organism for axis formation, asymmetric Wnt signaling is achieved by the differential localization of maternally derived molecules stored in the egg. These determinants are translocated toward the future dorsal side by microtubule-based rotational movements of the egg cortex following fertilization. Interference with this process results in embryos lacking the dorsal tissues. The exact mechanisms regulating asymmetry in cortical rotation and Wnt activation in axis formation remain unclear. Data from maternal loss-of- function studies, including preliminary studies for this proposal, have implicated vegetally localized factors. The long-term goal of this research is to understand the role of these localized maternal gene products in embryonic axis formation. Preliminary studies for this proposal have identified a potential for maternal Wnt signals in regulating cortical rotation. Novel methods for monitoring microtubule dynamics during cortical rotation in vivo are also employed. The objectives of this proposal are to determine mechanisms underlying the formation of the vegetal microtubule array and to characterize potential determinants carried on the array. The specific aims are to determine the roles of localized mRNAs in controlling microtubule assembly during the cortical rotation, to determine the extent this process is regulated by ongoing Wnt signaling in the oocyte and to characterize protein determinants in the vegetal cortex.