Study of asymmetric division in development

不对称分裂是在发育过程中产生细胞多样性的基本机制，并且通常通过将细胞命运决定子不对称分配到两个子细胞之一中来实现。果蝇神经干细胞（神经母细胞）作为一个模型系统被研究，研究了这一过程的关键方面，因为神经命运决定因子如Numb和Prospero被分离到神经母细胞分裂产生的两个子细胞之一中。与神经母细胞不对称分裂相关的两个重要过程是（1）细胞命运决定因子的不对称定位，这是通过特定的衔接蛋白如米兰达来实现的，这些衔接蛋白本身不对称地定位于皮层，和（2）有丝分裂纺锤体的取向及其与决定簇的极化定位的协调，这需要顶端的Baz-Insc-Pins复合物。为了理解成神经细胞不对称分裂的细胞极性，我们筛选了影响米兰达定位的突变，并揭示了一种以前未鉴定的机制，该机制负责成神经细胞分裂期间所有已知细胞命运决定子的不对称定位。这种机制涉及两种皮质肿瘤抑制蛋白的级联反应，即Lethal（2）巨大幼虫（Lgl）和Lethal（1）大碟（Dlg），并且发生在第一个不对称分裂方面的上游，独立于这两个方面的第二个。Lgl和Dlg通过在有丝分裂期间介导差异皮质蛋白靶向而在同胞细胞之间产生内在差异，首次证明了这些肿瘤抑制蛋白与神经干细胞的不对称分裂之间的联系。

Asymmetric division is a basic mechanism for generating cellular diversity during development, and is often achieved by the asymmetric partition of cell fate determinants into one of two daughter cells. The Drosophila neural stem cells, neuroblasts, have been studied as a model system with which to investigate key aspects of this process, given that neural fate determinants such as Numb and Prospero are segregated into one of the two daughter cells generated by neuroblast division.Two important processes associated with the asymmetric division of neuroblasts are (1) the asymmetric localization of cell fate determinants, which is achieved by specific adapter proteins such as Miranda that themselves localize asymmetrically to the cortex, and (2) the orientation of the mitotic spindle and its coordination with the polarized localization of the determinants, which require the apical Baz-Insc-Pins complex.To understand the cell polarity underlying the asymmetric division of neuroblasts, we have screened for mutations that affect the localization of Miranda, and have revealed a previously unidentified mechanism responsible for the asymmetric localization of all known cell fate determinants during neuroblast division. This mechanism involves a cascade of two cortical tumor suppressor proteins, Lethal (2) giant larvae (Lgl) and Lethal (1) discs large (Dlg), and occurs upstream of the first and independently of the second of these two aspects of asymmetric division. Lgl and Dlg create intrinsic differences between sibling cells by mediating differential cortical protein targeting during mitosis, demonstrating for the first time a link between these tumor suppressor proteins and the asymmetric division of neural stem cells.