Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts.
Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts.
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发表时间：
2002-10
期刊：
影响因子：
4.6
通讯作者：
Q. Shen;W. Zhong;Y. Jan;S. Temple
中科院分区：
文献类型：
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作者：
Q. Shen;W. Zhong;Y. Jan;S. Temple
来自小鼠胚胎的干细胞和神经母细胞经历重复的不对称细胞分裂，产生与无脊椎动物相似的神经谱系树。在果蝇中，有丝分裂期间 Numb 蛋白的不均匀分布会产生不对称的细胞分裂，从而导致不同的神经细胞命运。我们研究了小鼠同源物 m-numb 在小鼠皮质发育过程中是否具有类似的作用。从小鼠胚胎皮质中分离出的祖细胞在体外进行下一次细胞分裂时被追踪。麻木分布在产生β-微管蛋白III（-）祖细胞和β-微管蛋白III（+）神经元细胞（P/N分裂）的不对称细胞分裂期间主要是不对称的，并且在产生两个神经元（N/N分裂）的分裂期间主要是对称的。与野生型相比，numb 敲除小鼠的细胞经历了明显更少的不对称 P/N 分裂，这表明 Numb 具有因果作用。当来自早期（E10）皮层的祖细胞经历 P/N 分裂时，两个子细胞都表达祖细胞标记 Nestin，表明它们处于不成熟状态，并且 Numb 以相似的频率分离成 P 或 N 子细胞。相比之下，当来自后来的 E13 皮质（在体内活跃神经发生期间）的祖细胞经历 P/N 分裂时，它们会产生 Nestin(+) 祖细胞和 Nestin(-) 神经元子细胞，并且 Numb 优先分离到神经元子细胞中。因此，在小鼠皮质神经发生过程中，如在果蝇神经发生过程中，Numb 的不对称分离可以抑制一个子代的 Notch 活性，从而诱导神经元分化。在产生两个神经元的末期分裂中，Numb 对称分布在大约 80% 的神经元对中，不对称分布在 20% 的神经元对中。我们发现 Numb 分布与形态之间存在显着关联：具有对称 Numb 的神经元对的大多数姐妹是相似的，而大多数具有不对称 Numb 的神经元对是不同的。使用 Numb 开发皮质神经元的过程比不使用 Numb 的要长。 Numb 由神经母细胞和干细胞表达，并且可以被两者不对称地分离。这些数据表明 Numb 在小鼠皮质发育过程中产生不对称细胞分裂和不同细胞命运方面发挥着重要作用。
Stem cells and neuroblasts derived from mouse embryos undergo repeated asymmetric cell divisions, generating neural lineage trees similar to those of invertebrates. In Drosophila, unequal distribution of Numb protein during mitosis produces asymmetric cell divisions and consequently diverse neural cell fates. We investigated whether a mouse homologue m-numb had a similar role during mouse cortical development. Progenitor cells isolated from the embryonic mouse cortex were followed as they underwent their next cell division in vitro. Numb distribution was predominantly asymmetric during asymmetric cell divisions yielding a beta-tubulin III(-) progenitor and a beta-tubulin III(+) neuronal cell (P/N divisions) and predominantly symmetric during divisions producing two neurons (N/N divisions). Cells from the numb knockout mouse underwent significantly fewer asymmetric P/N divisions compared to wild type, indicating a causal role for Numb. When progenitor cells derived from early (E10) cortex undergo P/N divisions, both daughters express the progenitor marker Nestin, indicating their immature state, and Numb segregates into the P or N daughter with similar frequency. In contrast, when progenitor cells derived from later E13 cortex (during active neurogenesis in vivo) undergo P/N divisions they produce a Nestin(+) progenitor and a Nestin(-) neuronal daughter, and Numb segregates preferentially into the neuronal daughter. Thus during mouse cortical neurogenesis, as in Drosophila neurogenesis, asymmetric segregation of Numb could inhibit Notch activity in one daughter to induce neuronal differentiation. At terminal divisions generating two neurons, Numb was symmetrically distributed in approximately 80% of pairs and asymmetrically in 20%. We found a significant association between Numb distribution and morphology: most sisters of neuron pairs with symmetric Numb were similar and most with asymmetric Numb were different. Developing cortical neurons with Numb had longer processes than those without. Numb is expressed by neuroblasts and stem cells and can be asymmetrically segregated by both. These data indicate Numb has an important role in generating asymmetric cell divisions and diverse cell fates during mouse cortical development.