Role of Nesprin-2 and RanBP2 in BICD2-associated brain developmental disorders.
Role of Nesprin-2 and RanBP2 in BICD2-associated brain developmental disorders.
复制标题
DOI：
10.1371/journal.pgen.1010642
复制
发表时间：
2023-03
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
Bicaudal D2(BICD2)负责将胞浆动力蛋白募集到不同形式的亚细胞货物中进行细胞内运输。人类BICD2基因突变已被发现导致常染色体显性遗传型脊髓性肌萎缩症(SMA-LED2)和大脑发育缺陷。后一种突变是否以及如何与我们和其他人确定的BICD2在脑发育中的作用有关仍鲜为人知。BICD2与核孔蛋白RanBP2相互作用，将动力蛋白募集到放射状胶质前体细胞(RGPS)的核膜(NE)中，介导其众所周知但神秘的细胞周期调控的动间核迁移(INM)行为，以及随后的分化形成皮质神经元。我们最近发现，BICD2也介导了有丝分裂后迁移神经元中NE dynein的募集，尽管是通过不同的相互作用因子Nesprin-2。在此，我们报道了Nesprin-2和RanBP2在体外竞争BICD2结合。为了测试这一行为的生理学意义，我们使用体外生化和体内电穿孔介导的脑发育测试来检查已知BICD2突变的影响。我们发现BICD2与RanBP2结合的能力与Nesprin-2在控制核迁移和神经元迁移行为方面的能力之间存在明显的关系。我们认为，在NE相互排斥的RanBP2-BICD2和Nesprin-2-BICD2相互作用在RGPS的INM行为和有丝分裂后神经元迁移中发挥着连续的关键作用，这些过程中的错误导致了特定的人脑畸形。BICD2基因突变已被发现会导致大脑发育缺陷，以及其他疾病，如伴有下肢优势的脊髓性肌萎缩症2(SMA-LED2)。尽管BICD2对人类疾病有影响，但BICD2相关疾病的根本原因仍不完全清楚。在大脑发育期间，BICD2通过与两种不同的核膜蛋白RanBP2和Nesprin-2相继作用，将动力蛋白招募到有丝分裂前和有丝分裂后神经细胞的核膜上。BICD2-dynein相互作用的转换是如何实现的，以及它的生理必要性已经成为理解大脑正常和异常发育的重要问题。为了回答这些问题，我们首先进行了生化分析，比较了RanBP2和Nesprin-2与BICD2的结合。我们发现RanBP2和Nesprin-2与BICD2区域内不同的位点结合，但它们的相互作用是相互排斥的。其次，我们通过在胚胎大鼠大脑中表达致病的BICD2变体来测试这两种机制的相对生理作用。我们发现，BICD2的S与RanBP2和Nesprin-2的结合能力控制着特定的脑发育步骤，而与这些NE蛋白结合的缺陷导致了与BICD2突变相关的特定脑畸形。
Bicaudal D2 (BICD2) is responsible for recruiting cytoplasmic dynein to diverse forms of subcellular cargo for their intracellular transport. Mutations in the human BICD2 gene have been found to cause an autosomal dominant form of spinal muscular atrophy (SMA-LED2), and brain developmental defects. Whether and how the latter mutations are related to roles we and others have identified for BICD2 in brain development remains little understood. BICD2 interacts with the nucleoporin RanBP2 to recruit dynein to the nuclear envelope (NE) of Radial Glial Progenitor cells (RGPs) to mediate their well-known but mysterious cell-cycle-regulated interkinetic nuclear migration (INM) behavior, and their subsequent differentiation to form cortical neurons. We more recently found that BICD2 also mediates NE dynein recruitment in migrating post-mitotic neurons, though via a different interactor, Nesprin-2. Here, we report that Nesprin-2 and RanBP2 compete for BICD2-binding in vitro. To test the physiological implications of this behavior, we examined the effects of known BICD2 mutations using in vitro biochemical and in vivo electroporation-mediated brain developmental assays. We find a clear relationship between the ability of BICD2 to bind RanBP2 vs. Nesprin-2 in controlling of nuclear migration and neuronal migration behavior. We propose that mutually exclusive RanBP2-BICD2 vs. Nesprin-2-BICD2 interactions at the NE play successive, critical roles in INM behavior in RGPs and in post-mitotic neuronal migration and errors in these processes contribute to specific human brain malformations. Mutations in BICD2 gene have been found to cause brain developmental defects, as well as other disorders, like Spinal Muscular Atrophy with Lower Extremity Dominance 2 (SMA-LED2). Despite its impact on human disorders, the underlying cause of BICD2 associated disease conditions remains incompletely understood. During brain development, BICD2 recruits dynein to the nuclear envelope of pre- and post-mitotic neuronal cells via successive interactions with two different nuclear envelope proteins, RanBP2 and Nesprin-2. How the switch in BICD2-dynein cargo interactions is achieved and its physiological necessity have emerged as important questions for understanding normal and abnormal brain development. To answer the questions, we first performed biochemical assays to compare RanBP2 and Nesprin-2 bindings to BICD2. We find that RanBP2 and Nesprin-2 bind to distinct sites within BICD2 region, but their interactions are mutually exclusive. Second, we test the relative physiological roles of the two mechanisms by expressing disease-causing BICD2 variants in embryonic rat brains. We find that BICD2’s ability to bind RanBP2 vs. Nesprin-2 controls specific brain developmental steps, and defects in the binding to these NE proteins contribute to the specific brain deformities associated with BICD2 mutations.
登录
查看更多内容
DOI：
10.1126/science.1254198
发表时间：
2014-07-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
McKenney RJ;Huynh W;Tanenbaum ME;Bhabha G;Vale RD
通讯作者：
Vale RD
影响因子：
11.8
作者：
Grigoriev, Ilya;Splinter, Daniel;Akhmanova, Anna
通讯作者：
Akhmanova, Anna
影响因子：
1.8
作者：
Koboldt, Daniel C.;Kastury, Rama D.;White, Peter
通讯作者：
White, Peter
影响因子：
9.8
作者：
Neveling, Kornelia;Martinez-Carrera, Lilian A.;Wirth, Brunhilde
通讯作者：
Wirth, Brunhilde
DOI：
10.1146/annurev-cellbio-100814-125438
发表时间：
2015
影响因子：
11.3
作者：
Cianfrocco MA;DeSantis ME;Leschziner AE;Reck-Peterson SL
通讯作者：
Reck-Peterson SL