摘要
细胞核的正常定位在多种生物学过程中起着重要作用,在人体内细胞核定位的失败能够导致严重疾病。细胞骨架微管和肌动蛋白都参与了细胞核定位的过程。近年来在线虫和果蝇中的研究表明,KASH/SUN两类核膜蛋白通过与不同细胞骨架的作用在细胞核的迁移和锚定中起着重要功能。虽然在体外培养的细胞中对哺乳动物中的KASH蛋白和SUN蛋白有一定的研究,但是两类核膜蛋白在小鼠体内的功能在很大程度上仍不清楚。本研究中,我们运用KASH蛋白Syne-1,Syne-2和SUN蛋白SUN1,SUN2的基因敲除小鼠,探讨了这四个基因在小鼠肌肉细胞核锚定和神经细胞迁移过程中的功能。
在哺乳动物的骨骼肌中,成百上千的细胞核均匀排布在细胞膜下方,仅在神经肌肉接头下有3—8个细胞核聚集(突触下细胞核)。虽然肌细胞核的特征性分布被认为有利于细胞质转运和维持神经肌肉接头的结构,但是其定位机制一直以来有待发掘。我们发现,Syne-1,Syne-2和SUN1,SUN2在肌肉中都定位在细胞核膜上。Syne-1的KASH功能域被敲除之后破坏了突触外肌细胞核的定位和突触下细胞核的聚集,后者进一步影响了与之相连的运动神经的正常发育。在肌肉中过量表达带有KASH功能域的Syne-2蛋白片段后能够干扰内源Syne-1蛋白的功能,从而破坏了突触下细胞核的锚定。SUN1和SUN2分别单独被敲除后对肌细胞核的定位没有影响,但是二者同时被敲除之后同样能够破坏肌肉细胞核的定位和运动神经的发育,而且二者在Syne-1的核膜定位中起着必须的且相互冗余的功能。上述结果表明Syne-1和SUN1,SUN2一起在肌细胞核的锚定中起着关键作用。
神经细胞迁移失败是导致多种严重人类疾病的重要原因,比如癫痫,智力发育异常和精神分裂症。细胞核迁移是神经细胞迁移过程中的关键步骤。核迁移中,微管和胞质动力蛋白是如何将迁移动力施加到细胞核的一直是一个非常重要的问题。我们发现,Syne-1,Syne-2双敲除(Syne DKO)小鼠和SUN1,SUN2双敲除(SUN DKO)小鼠在出生后都因无法呼吸而很快死亡,而且两种双敲除小鼠的大脑显著变小。组织学分析发现,两种双敲除小鼠的皮层发育严重受损,无法正常分层。细胞迁移追踪实验结果表明,Syne-1,Syne-2双敲除和SUN1,SUN2双敲除分别造成了辐射方向神经细胞迁移的失败。结合Syne和SUN蛋白在核膜上与胞质动力蛋白和Lis1的定位关系,我们提出Syne-1,Syne-2和SUN1,SUN2很可能提供了胞质动力蛋白在细胞核膜上的锚定位点,从而介导微管系统向细胞核施加的迁移动力。
我们对Syne-1,Syne-2和SUNl,SUN2在小鼠体内的生物功能研究揭示了它们在至少两类细胞核定位中的重要作用,即骨骼肌细胞核的锚定和大脑皮层神经元的辐射方向迁移。本研究的结果不仅丰富了对细胞核锚定和迁移的分子机制的研究,而且增进了对肌无力和神经系统病症等人类疾病发病机理的认识。
Nuclear positioning is essential for many biological processes, defects of which can cause severe human diseases. Both microtubule and actin cytoskeleton have been shown to be involved in proper nuclear positioning. Recent pivotal studies in C.elegans and Drosophila have demonstrated that KASH proteins and SUN proteins, two kinds of nuclear envelope (NE) proteins, play critical roles in nuclear migration and anchorage through interaction with different sets of cytoskeletons. Although several kinds of functions of mammalian KASH and SUN proteins have been reported using in vitro tissue culture cells, their essential in vivo functions remain largely unknown. Using knockout mice against Syne-1, Syne-2 and SUN1, SUN2, we have studied their functions during myonuclear anchorage and neuronal migration in this research.
Each skeletal muscle cell of mammals contains hundreds of nuclei which are evenly spaced beneath the cell membrane, except for 3～8 synaptic nuclei clustering under the neuromuscular junction (NMJ). The arrangement of myonuclei has been thought to be essential for intracellular transport and NMJ structure maintenance for many years. However, the underlying mechanism of nuclear positioning remains unclear. We found that all four proteins were localized on the NE of myonuclei. The deletion of Syne-1 KASH domain completely disrupted the anchorage of myonuclei and the clustering of synaptic nuclei, which in turn affected the innervation of motor nerves. The overexpression of Syne-2 KASH domain caused a similar nuclear anchorage defect through disturbing the function of endogenous Syne-1. Although the deletion of either SUN 1 or SUN2 did not affect myonuclear positioning, the double knockout of SUN proteins disrupted the anchorage of mynuclei and the branching process of motor nerves through abolishing the NE localization of Syne-1. These results demonstrated that Syne-1, together with SUN1 and SUN2 are essential for myonuclear positioning.
Neuronal migration failure is an important cause for many kinds of severe human diseases, such as epilepsy, mental retardation and schizophrenia. Nucleokinesis is a key process of neuronal migration. However, it has long been a question mark how the pulling force is transfered from microtubule and dynein to the "huge" nucleus. In this research, we found the Syne DKO and SUN DKO mice were succefully delivered but died soon after birth from breath failure. The brains of Syne DKO or SUN DKO mice were significantly smaller than their littermate controls. Histological analysis showed that the cerebral cortex of Syne DKO and SUN DKO mice displayed severe laminary defects. Birth-dating experiments demonstrated that both Syne DKO and SUN DKO disrupted the radial neuronal migration in the cerebral cortex. Furthermore, we showed that Syne-1 and Syne-2 colocalized with Lis1/dynein complex both in vivo and in vitro. Based on these observations, we propose that Syne-1 and Syne-2 are the potential nuclear envelope binding sites of Lis1/dynein complex, with which Syne and SUN proteins mediate the coupling between microtubule and the nucleus during neuronal migration.
Our studies on Syne-1, Syne-2 and SUN1, SUN2 discovered their crucial functions during myonuclear anchorage and neuronal migration. These results could advance our knowledge on the molecular mechanism of nuclear positioning, and provide new insights into the pathology of human muscular dystrophy and mental diseases.
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