The role of mitotic asymmetries for Wnt and Bmp signaling

WNT信号在胚胎干细胞中是活跃的，在胚胎发育过程中对前-后(头-尾)轴的建立非常重要。BMP信号控制背腹(后腹部)轴，Wnt和BMP一起在胚胎中创建笛卡尔坐标系。在BMP转录因子Smad1的水平上已经显示出相互作用，其降解被Wnt信号阻止。重要的是，Smad1和许多其他被标记为通过磷酸化降解的蛋白质不均匀地积累在分裂胚胎细胞和体细胞的细胞核附近。因此，其中一个子细胞继承了更多的相关蛋白质，这引发了对这一机制的调节及其对细胞分裂和胚胎发育功能的质疑。在初步的细胞系实验中，我们发现WNT处理后这种不对称分选过程显着增加。重要的是，这也导致激活的信号成分在相应细胞的细胞核中不对称地积累。在这个项目中，我将首先调查Wnt信号对细胞不对称性的影响的本质。作为第二部分，我将使用不同的方法分析这些不对称性是否反映了两个子细胞信号活性的差异。揭示Wnt和BMP信号是否也是不对称的，这意味着子代细胞的不同命运，这将是非常重要的。最后，这些分析将扩展到胚胎，以揭示这是否是细胞分裂的普遍极性现象，并将这些特征与Wnt和Bmp对轴发育的整体调控联系起来。总而言之，这个项目将有助于解释在细胞分裂过程中做出的一般二元决定是如何与复杂胚胎的胚轴发育相关的。

Wnt signaling is active in embryonic stem cells and important for anterior-posterior (head-tail) axis establishment during embryogenesis. Bmp signaling controls the dorso-ventral (back-belly) axis and together Wnt and Bmp create a Cartesian coordinate system in the embryo. Intercommunication has been shown at the level of the Bmp transcription factor Smad1, whose degradation is prevented by Wnt signals. Importantly, Smad1 and many other proteins tagged for degradation by phosphorylation unequally accumulate near the cell nucleus of dividing embryonic and somatic cells. Thus, one of the daughter cell inherits more of the relevant proteins, raising questions about the regulation of this mechanism and its function for cell divisions and embryonic development. In preliminary cell line experiments we found this process of asymmetric sorting significantly increased by Wnt treatment. Importantly, this caused asymmetric accumulation of activated signaling components in the nucleus of the corresponding cell as well. In this project, I will first investigate the nature of the influence of Wnt signals on cellular asymmetries. As a second part, I will analyze if these asymmetries reflect differences in signaling activity of two daughter cells by using different approaches. It would be of great importance to reveal if Wnt and Bmp signaling are asymmetric as well, implying different fates for the daughter cells. Finally, these analyses will be extended to embryos to uncover if this is a general polarity phenomenon of dividing cells and to connect the features with overall regulation of axis development by Wnt and Bmp. In sum, this project will help to explain how general binary decisions made during cell division are related to embryonic axis development in complex embryos.