NUDC(核分布蛋白C)是参与跨物种的核迁移和胞质分裂的有丝分裂蛋白。被认为是细胞质动力蛋白(以下称为动力蛋白)辅因子,NUDC在神经元迁移过程中与动力蛋白运动复合物相关。NUDC也在有丝分裂后的脊椎动物杆状光感受器中表达,其功能未知。这里,我们通过研究小鼠杆中条件性NUDC敲除(rNudC-/-)的后果,研究了NUDC在有丝分裂后杆状光感受器中的作用。棒中NUDC的丢失导致6周龄时感光细胞完全死亡。3周龄时,rNudC-/-功能减弱,视紫红质和线粒体定位错误,与动力蛋白抑制一致。外段蛋白水平降低,但LIS1(肝脑蛋白1),一种特征明确的动力蛋白辅因子,未受影响。透射电子显微镜显示,到3周龄时,rNudC-/-棒内存在超微结构缺陷。我们调查了NUDC是否与肌动蛋白调节剂cofilin1(CFL1)相互作用,发现在棒中,CFL1位于NUDC附近。除了它在棒体内的动力蛋白贩运中的潜在作用外,NUDC的损失也导致磷酸化CFL1(pCFL1)的水平增加,据称可以防止肌动蛋白的解聚。NUDC的缺失也在3周龄时诱导了Müller胶质细胞和神经视网膜上的小胶质细胞的炎症反应。一起来看,我们的数据说明了NUDC在有丝分裂后杆状光感受器中肌动蛋白细胞骨架维持和动力蛋白介导的蛋白质运输中的关键作用。
NUDC (nuclear distribution protein C) is a mitotic protein involved in nuclear migration and cytokinesis across species. Considered a cytoplasmic
dynein (henceforth
dynein) cofactor, NUDC was shown to associate with the
dynein motor complex during neuronal migration. NUDC is also expressed in postmitotic vertebrate rod photoreceptors where its function is unknown. Here, we examined the role of NUDC in postmitotic rod photoreceptors by studying the consequences of a conditional NUDC knockout in mouse rods (rNudC-/- ). Loss of NUDC in rods led to complete photoreceptor cell death at 6 weeks of age. By 3 weeks of age, rNudC-/- function was diminished, and rhodopsin and mitochondria were mislocalized, consistent with
dynein inhibition. Levels of outer segment proteins were reduced, but LIS1 (lissencephaly protein 1), a well-characterized
dynein cofactor, was unaffected. Transmission electron microscopy revealed ultrastructural defects within the rods of rNudC-/- by 3 weeks of age. We investigated whether NUDC interacts with the actin modulator cofilin 1 (CFL1) and found that in rods, CFL1 is localized in close proximity to NUDC. In addition to its potential role in
dynein trafficking within rods, loss of NUDC also resulted in increased levels of phosphorylated CFL1 (pCFL1), which would purportedly prevent depolymerization of actin. The absence of NUDC also induced an inflammatory response in Müller glia and microglia across the neural retina by 3 weeks of age. Taken together, our data illustrate the critical role of NUDC in actin cytoskeletal maintenance and
dynein-mediated protein trafficking in a postmitotic rod photoreceptor.