<br>NUDC 对于视杆细胞感光功能、维持和存活至关重要,The FASEB Journal

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NUDC 对于视杆细胞感光功能、维持和存活至关重要
The FASEB Journal ( IF 4.4 ) Pub Date : 2024-03-05 , DOI: 10.1096/fj.202301641rr
Mary Anne Garner ₁ , Meredith G Hubbard ₁ , Evan R Boitet ₁ , Seth T Hubbard ₁ , Anushree Gade ₁ , Guoxin Ying ₂ , Bryan W Jones ₂ , Wolfgang Baehr ₂ , Alecia K Gross ₁

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NUDC（核分布蛋白C ）是一种有丝分裂蛋白，参与跨物种的核迁移和胞质分裂。 NUDC 被认为是细胞质动力蛋白（下文称为动力蛋白）辅助因子，在神经元迁移过程中与动力蛋白运动复合体相关。 NUDC 也在有丝分裂后的脊椎动物视杆细胞中表达，但其功能尚不清楚。在这里，我们通过研究条件性 NUDC 敲除小鼠视杆细胞 (r NudC ^−/− ) 的后果，研究了 NUDC 在有丝分裂后视杆细胞光感受器中的作用。视杆细胞中 NUDC 的缺失导致 6 周龄时感光细胞完全死亡。到 3 周龄时，r NudC ^-/−功能减弱，视紫红质和线粒体定位错误，这与动力蛋白抑制一致。外节蛋白水平降低，但 LIS1（无脑畸形蛋白 1）（一种充分表征的动力蛋白辅因子）不受影响。透射电子显微镜显示 r NudC ^−/− 3 周龄时杆体内存在超微结构缺陷。我们研究了 NUDC 是否与肌动蛋白调节剂 cofilin 1 (CFL1) 相互作用，并发现在杆状细胞中，CFL1 定位于靠近 NUDC 的位置。除了其在杆内动力蛋白运输中的潜在作用外，NUDC 的缺失还导致磷酸化 CFL1 (pCFL1) 水平增加，据称这会阻止肌动蛋白解聚。 3周龄时，缺乏 NUDC 还会诱导整个神经视网膜的穆勒胶质细胞和小胶质细胞发生炎症反应。综上所述，我们的数据说明了 NUDC 在肌动蛋白细胞骨架维持和有丝分裂后视杆光感受器中动力蛋白介导的蛋白质运输中的关键作用。

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NUDC is critical for rod photoreceptor function, maintenance, and survival

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.

更新日期：2024-03-05

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