基于血影蛋白的膜骨架调控神经发育的机理研究

破坏基于血影蛋白spectrin的细胞膜骨架生物力学会导致遗传性椭圆形红细胞增多症和脊髓小脑性共济失调，但我们对发病机理和发病的细胞学基础还知之甚少。我们以秀丽隐杆线虫作为疾病模型，在线虫保守的alpha-和beta-spectrin基因中引入两个疾病相关的突变，在线虫幼虫研究spectrin对神经细胞迁移和树突形成的调控作用。前期工作发现spectrin的功能缺失导致微丝骨架在前导端外的区域异常聚合，产生次生细胞膜突起，最终导致神经细胞迁移不到位和形态缺陷。Spectrin在迁移神经细胞的侧面和后部富集，继而从神经元胞体转移至新生长的树突中，表明基于spectrin的细胞膜骨架不对称地和动态地调控微丝骨架组装。Spectrin的亲和纯化发现结合蛋白ankyrin与spectrin协同合作。本课题的研究成果提示细胞膜骨架在不同的发育进程中的极性分布和动态重塑可以在时空维度调控细胞膜力学。

Perturbation of spectrin-based membrane biomechanics causes hereditary elliptocytosis and spinocerebellar ataxia, but the underlying cellular basis of pathogenesis remains unclear. Here, we introduced the conserved disease-associated spectrin mutations into the C. elegans genome and studied the contribution of spectrin to neuronal migration and dendrite formation in developing larvae. Our preliminary results found the loss of spectrin generates an ectopic actin polymerization outside of the existing front and secondary membrane protrusions, leading to defective neuronal positioning and dendrite morphology in adult animals. Spectrin accumulates in the lateral and the rear of migrating neuroblasts and redistributes from the soma into the newly formed dendrites, indicating that the spectrin-based membrane skeleton is asymmetric and remodels to regulate actin assembly and cell shape during development. We affinity-purified spectrin from C. elegans and showed that its binding partner ankyrin functions with spectrin. Our results suggest asymmetry and remodeling of membrane skeleton may enable spatiotemporal modulation of membrane mechanics for distinct developmental events.