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A genome-wide screen links peroxisome regulation with Wnt signaling through RNF146 and TNKS/2. 一项全基因组筛选通过 RNF146 和 TNKS/2 将过氧物酶体调控与 Wnt 信号传导联系起来。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-07-05 DOI: 10.1083/jcb.202312069
Jonathan T Vu, Katherine U Tavasoli, Connor J Sheedy, Soham P Chowdhury, Lori Mandjikian, Julien Bacal, Meghan A Morrissey, Chris D Richardson, Brooke M Gardner

Peroxisomes are membrane-bound organelles harboring metabolic enzymes. In humans, peroxisomes are required for normal development, yet the genes regulating peroxisome function remain unclear. We performed a genome-wide CRISPRi screen to identify novel factors involved in peroxisomal homeostasis. We found that inhibition of RNF146, an E3 ligase activated by poly(ADP-ribose), reduced the import of proteins into peroxisomes. RNF146-mediated loss of peroxisome import depended on the stabilization and activity of the poly(ADP-ribose) polymerases TNKS and TNKS2, which bind the peroxisomal membrane protein PEX14. We propose that RNF146 and TNKS/2 regulate peroxisome import efficiency by PARsylation of proteins at the peroxisome membrane. Interestingly, we found that the loss of peroxisomes increased TNKS/2 and RNF146-dependent degradation of non-peroxisomal substrates, including the β-catenin destruction complex component AXIN1, which was sufficient to alter the amplitude of β-catenin transcription. Together, these observations not only suggest previously undescribed roles for RNF146 in peroxisomal regulation but also a novel role in bridging peroxisome function with Wnt/β-catenin signaling during development.

过氧物酶体是一种膜结合细胞器,内含代谢酶。人类的正常发育需要过氧物酶体,但调节过氧物酶体功能的基因仍不清楚。我们进行了全基因组 CRISPRi 筛选,以鉴定参与过氧物酶体稳态的新因子。我们发现,抑制 RNF146(一种由聚(ADP-核糖)激活的 E3 连接酶)会减少蛋白质向过氧化物酶体的输入。RNF146 介导的过氧化物酶体导入损失取决于多(ADP-核糖)聚合酶 TNKS 和 TNKS2 的稳定和活性,而 TNKS2 与过氧化物酶体膜蛋白 PEX14 结合。我们认为,RNF146 和 TNKS/2 通过过氧化物酶体膜上蛋白的 PARsylation 来调节过氧化物酶体的导入效率。有趣的是,我们发现过氧化物酶体的缺失增加了 TNKS/2 和 RNF146 对非过氧化物酶体底物的依赖性降解,包括 β-catenin破坏复合体成分 AXIN1,这足以改变 β-catenin转录的幅度。这些观察结果表明,RNF146不仅在过氧化物酶体调控中发挥了以前未曾描述过的作用,而且在发育过程中还在连接过氧化物酶体功能与Wnt/β-catenin信号方面发挥了新的作用。
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引用次数: 0
AMPK activation induces RALDH+ tolerogenic dendritic cells by rewiring glucose and lipid metabolism. AMPK 激活可通过重构葡萄糖和脂质代谢诱导 RALDH+耐受性树突状细胞。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-08-08 DOI: 10.1083/jcb.202401024
Eline C Brombacher, Thiago A Patente, Alwin J van der Ham, Tijmen J A Moll, Frank Otto, Fenne W M Verheijen, Esther A Zaal, Arnoud H de Ru, Rayman T N Tjokrodirijo, Celia R Berkers, Peter A van Veelen, Bruno Guigas, Bart Everts

Dendritic cell (DC) activation and function are underpinned by profound changes in cellular metabolism. Several studies indicate that the ability of DCs to promote tolerance is dependent on catabolic metabolism. Yet the contribution of AMP-activated kinase (AMPK), a central energy sensor promoting catabolism, to DC tolerogenicity remains unknown. Here, we show that AMPK activation renders human monocyte-derived DCs tolerogenic as evidenced by an enhanced ability to drive differentiation of regulatory T cells, a process dependent on increased RALDH activity. This is accompanied by several metabolic changes, including increased breakdown of glycerophospholipids, enhanced mitochondrial fission-dependent fatty acid oxidation, and upregulated glucose catabolism. This metabolic rewiring is functionally important as we found interference with these metabolic processes to reduce to various degrees AMPK-induced RALDH activity as well as the tolerogenic capacity of moDCs. Altogether, our findings reveal a key role for AMPK signaling in shaping DC tolerogenicity and suggest AMPK as a target to direct DC-driven tolerogenic responses in therapeutic settings.

树突状细胞(DC)的活化和功能是由细胞代谢的深刻变化支撑的。一些研究表明,树突状细胞促进耐受的能力取决于分解代谢。然而,促进新陈代谢的中心能量传感器 AMPK 对 DC 耐受性的贡献仍然未知。在这里,我们发现 AMPK 激活可使人类单核细胞衍生的 DC 产生耐受性,这表现在驱动调节性 T 细胞分化的能力增强,而这一过程依赖于 RALDH 活性的增加。与此同时,新陈代谢也发生了一些变化,包括甘油磷脂分解增加、线粒体裂变依赖性脂肪酸氧化增强以及葡萄糖分解代谢上调。这种代谢重构在功能上非常重要,因为我们发现干扰这些代谢过程会在不同程度上降低 AMPK 诱导的 RALDH 活性以及 moDCs 的耐受能力。总之,我们的研究结果揭示了 AMPK 信号在形成直流耐受性中的关键作用,并建议将 AMPK 作为治疗环境中指导直流驱动的耐受性反应的靶点。
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引用次数: 0
An evolutionarily conserved AnkyrinG-dependent motif clusters axonal K2P K+ channels. 轴突 K2P K+ 通道的一个进化保守的 AnkyrinG 依赖性基团。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-07-30 DOI: 10.1083/jcb.202401140
Gabriel Escobedo, Yu Wu, Yuki Ogawa, Xiaoyun Ding, Matthew N Rasband

The evolution of ion channel clustering at nodes of Ranvier enabled the development of complex vertebrate nervous systems. At mammalian nodes, the K+ leak channels TRAAK and TREK-1 underlie membrane repolarization. Despite the molecular similarities between nodes and the axon initial segment (AIS), TRAAK and TREK-1 are reportedly node-specific, suggesting a unique clustering mechanism. However, we show that TRAAK and TREK-1 are enriched at both nodes and AIS through a common mechanism. We identified a motif near the C-terminus of TRAAK that is necessary and sufficient for its clustering. The motif first evolved among cartilaginous fish. Using AnkyrinG (AnkG) conditional knockout mice, CRISPR/Cas9-mediated disruption of AnkG, co-immunoprecipitation, and surface recruitment assays, we show that TRAAK forms a complex with AnkG and that AnkG is necessary for TRAAK's AIS and nodal clustering. In contrast, TREK-1's clustering requires TRAAK. Our results expand the repertoire of AIS and nodal ion channel clustering mechanisms and emphasize AnkG's central role in assembling excitable domains.

兰维耶结点离子通道集群的进化使复杂的脊椎动物神经系统得以发展。在哺乳动物的节点处,K+泄漏通道TRAAK和TREK-1是膜再极化的基础。尽管节点和轴突起始节段(AIS)之间存在分子相似性,但据报道 TRAAK 和 TREK-1 具有节点特异性,这表明它们具有独特的集群机制。然而,我们的研究表明,TRAAK 和 TREK-1 是通过一种共同的机制富集于节点和 AIS 的。我们在 TRAAK 的 C 端附近发现了一个对其聚类十分必要和充分的基团。该基调首先在软骨鱼类中进化。利用AnkyrinG(AnkG)条件性基因敲除小鼠、CRISPR/Cas9介导的AnkG干扰、共免疫沉淀和表面招募试验,我们发现TRAAK与AnkG形成了复合物,并且AnkG是TRAAK的AIS和结节集群所必需的。相反,TREK-1的聚类需要TRAAK。我们的研究结果扩大了AIS和节点离子通道聚类机制的范围,并强调了AnkG在组装可兴奋结构域中的核心作用。
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引用次数: 0
Integrated stress response activator halofuginone protects mice from diabetes-like phenotypes. 综合应激反应激活剂卤夫酮可保护小鼠免受糖尿病样表型的影响。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-08-16 DOI: 10.1083/jcb.202405175
Shashank Rai, Maria Szaruga, Aleksandra P Pitera, Anne Bertolotti

The integrated stress response (ISR) is a vital signaling pathway initiated by four kinases, PERK, GCN2, HRI and PKR, that ensure cellular resilience and protect cells from challenges. Here, we investigated whether increasing ISR signaling could rescue diabetes-like phenotypes in a mouse model of diet-induced obesity (DIO). We show that the orally available and clinically approved GCN2 activator halofuginone (HF) can activate the ISR in mouse tissues. We found that daily oral administration of HF increases glucose tolerance whilst reducing weight gain, insulin resistance, and serum insulin in DIO mice. Conversely, the ISR inhibitor GSK2656157, used at low doses to optimize its selectivity, aggravates glucose intolerance in DIO mice. Whilst loss of function mutations in mice and humans have revealed that PERK is the essential ISR kinase that protects from diabetes, our work demonstrates the therapeutic value of increasing ISR signaling by activating the related kinase GCN2 to reduce diabetes phenotypes in a DIO mouse model.

综合应激反应(ISR)是由四种激酶(PERK、GCN2、HRI 和 PKR)启动的重要信号通路,可确保细胞恢复能力并保护细胞免受挑战。在这里,我们研究了增加 ISR 信号传导是否能挽救饮食诱导肥胖(DIO)小鼠模型中的糖尿病样表型。我们的研究表明,可口服且已获临床批准的 GCN2 激活剂卤夫酮 (HF) 能激活小鼠组织中的 ISR。我们发现,每天口服 HF 可增加葡萄糖耐量,同时减少 DIO 小鼠的体重增加、胰岛素抵抗和血清胰岛素。相反,低剂量使用以优化其选择性的 ISR 抑制剂 GSK2656157 会加重 DIO 小鼠的葡萄糖耐受性。虽然小鼠和人类的功能缺失突变揭示了 PERK 是防止糖尿病的重要 ISR 激酶,但我们的工作证明了通过激活相关激酶 GCN2 来增加 ISR 信号的治疗价值,从而减少 DIO 小鼠模型中的糖尿病表型。
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引用次数: 0
Synaptotagmin-1 undergoes phase separation to regulate its calcium-sensitive oligomerization. 突触表蛋白-1通过相分离来调节其钙敏感性寡聚。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-07-09 DOI: 10.1083/jcb.202311191
Min Zhu, Han Xu, Yulei Jin, Xiaoxu Kong, Bingkuan Xu, Yinghui Liu, Haijia Yu

Synaptotagmin-1 (Syt1) is a calcium sensor that regulates synaptic vesicle fusion in synchronous neurotransmitter release. Syt1 interacts with negatively charged lipids and the SNARE complex to control the fusion event. However, it remains incompletely understood how Syt1 mediates Ca2+-trigged synaptic vesicle fusion. Here, we discovered that Syt1 undergoes liquid-liquid phase separation (LLPS) to form condensates both in vitro and in living cells. Syt1 condensates play a role in vesicle attachment to the PM and efficiently recruit SNAREs and complexin, which may facilitate the downstream synaptic vesicle fusion. We observed that Syt1 condensates undergo a liquid-to-gel-like phase transition, reflecting the formation of Syt1 oligomers. The phase transition can be blocked or reversed by Ca2+, confirming the essential role of Ca2+ in Syt1 oligomer disassembly. Finally, we showed that the Syt1 mutations causing Syt1-associated neurodevelopmental disorder impair the Ca2+-driven phase transition. These findings reveal that Syt1 undergoes LLPS and a Ca2+-sensitive phase transition, providing new insights into Syt1-mediated vesicle fusion.

突触标签蛋白-1(Syt1)是一种钙传感器,在神经递质同步释放过程中调节突触囊泡的融合。Syt1 与带负电荷的脂质和 SNARE 复合物相互作用,控制融合过程。然而,人们对 Syt1 如何介导 Ca2+ 触发的突触囊泡融合仍不甚了解。在这里,我们发现 Syt1 在体外和活细胞中都会发生液-液相分离(LLPS),形成凝聚物。Syt1凝聚物在囊泡附着到PM上发挥作用,并能有效招募SNAREs和复合素,这可能会促进下游突触囊泡的融合。我们观察到,Syt1凝聚物经历了从液态到凝胶状的相变,这反映了Syt1低聚物的形成。这种相变可被 Ca2+ 阻断或逆转,证实了 Ca2+ 在 Syt1 寡聚体解体过程中的重要作用。最后,我们发现,导致Syt1相关神经发育障碍的Syt1突变会损害Ca2+驱动的相变。这些发现揭示了Syt1经历了LLPS和Ca2+敏感的相变,为Syt1介导的囊泡融合提供了新的见解。
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引用次数: 0
LYSMD proteins promote activation of Rab32-family GTPases for lysosome-related organelle biogenesis. LYSMD蛋白可促进Rab32家族GTP酶的活化,从而促进溶酶体相关细胞器的生物生成。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-07-30 DOI: 10.1083/jcb.202402016
Jinglin Li, Qiuyuan Yin, Nan Xuan, Qiwen Gan, Chaolian Liu, Qian Zhang, Mei Yang, Chonglin Yang

Lysosome-related organelles (LROs) are specialized lysosomes with cell type-specific roles in organismal homeostasis. Dysregulation of LROs leads to many human disorders, but the mechanisms underlying their biogenesis are not fully understood. Here, we identify a group of LYSMD proteins as evolutionarily conserved regulators of LROs. In Caenorhabditis elegans, mutations of LMD-2, a LysM domain-containing protein, reduce the levels of the Rab32 GTPase ortholog GLO-1 on intestine-specific LROs, the gut granules, leading to their abnormal enlargement and defective biogenesis. LMD-2 interacts with GLO-3, a subunit of GLO-1 guanine nucleotide exchange factor (GEF), thereby promoting GLO-1 activation. Mammalian homologs of LMD-2, LYSMD1, and LYSMD2 can functionally replace LMD-2 in C. elegans. In mammals, LYSMD1/2 physically interact with the HPS1 subunit of BLOC-3, the GEF of Rab32/38, thus promoting Rab32 activation. Inactivation of both LYSMD1 and LYSMD2 reduces Rab32 activation, causing melanosome enlargement and decreased melanin production in mouse melanoma cells. These findings provide important mechanistic insights into LRO biogenesis and functions.

溶酶体相关细胞器(LROs)是特化的溶酶体,在机体平衡中具有细胞类型特异性的作用。溶酶体相关细胞器的失调会导致许多人类疾病,但它们的生物发生机制尚未完全明了。在这里,我们发现一组 LYSMD 蛋白是进化保守的 LROs 调节因子。在秀丽隐杆线虫(Caenorhabditis elegans)中,LMD-2(一种含LysM结构域的蛋白)的突变会降低肠道特异性LRO(肠道颗粒)上的Rab32 GTP酶同源物GLO-1的水平,导致其异常增大和生物发生缺陷。LMD-2 与 GLO-1 的鸟嘌呤核苷酸交换因子(GEF)亚基 GLO-3 相互作用,从而促进 GLO-1 的活化。哺乳动物中 LMD-2 的同源物 LYSMD1 和 LYSMD2 可以在功能上替代 elegans 中的 LMD-2。在哺乳动物中,LYSMD1/2 与 Rab32/38 的 GEF BLOC-3 的 HPS1 亚基发生物理作用,从而促进 Rab32 的活化。LYSMD1 和 LYSMD2 失活会降低 Rab32 的活化,导致小鼠黑色素瘤细胞中黑色素体增大和黑色素生成减少。这些发现提供了有关 LRO 生物发生和功能的重要机理见解。
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引用次数: 0
Small GTPase ActIvitY ANalyzing (SAIYAN) system: A method to detect GTPase activation in living cells. 小 GTPase 活性分析(SAIYAN)系统:一种检测活细胞中 GTP 酶活化的方法。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-08-05 DOI: 10.1083/jcb.202403179
Miharu Maeda, Masashi Arakawa, Yukie Komatsu, Kota Saito

Small GTPases are essential in various cellular signaling pathways, and detecting their activation within living cells is crucial for understanding cellular processes. The current methods for detecting GTPase activation using fluorescent proteins rely on the interaction between the GTPase and its effector. Consequently, these methods are not applicable to factors, such as Sar1, where the effector also functions as a GTPase-activating protein. Here, we present a novel method, the Small GTPase ActIvitY ANalyzing (SAIYAN) system, for detecting the activation of endogenous small GTPases via fluorescent signals utilizing a split mNeonGreen system. We demonstrated Sar1 activation at the endoplasmic reticulum (ER) exit site and successfully detected its activation state in various cellular conditions. Utilizing the SAIYAN system in collagen-secreting cells, we discovered activated Sar1 localized both at the ER exit sites and ER-Golgi intermediate compartment (ERGIC) regions. Additionally, impaired collagen secretion confined the activated Sar1 at the ER exit sites, implying the importance of Sar1 activation through the ERGIC in collagen secretion.

小 GTP 酶在各种细胞信号通路中至关重要,检测它们在活细胞内的激活情况对于了解细胞过程至关重要。目前使用荧光蛋白检测 GTP 酶活化的方法依赖于 GTP 酶与其效应物之间的相互作用。因此,这些方法不适用于Sar1等因子,因为在这些因子中,效应物也起着GTP酶激活蛋白的作用。在这里,我们提出了一种新方法--小 GTPase ActIvitY ANalyzing(SAIYAN)系统,它可以利用分裂的 mNeonGreen 系统通过荧光信号检测内源性小 GTPase 的活化。我们证明了 Sar1 在内质网(ER)出口部位的活化,并成功检测了其在各种细胞条件下的活化状态。在分泌胶原蛋白的细胞中利用 SAIYAN 系统,我们发现活化的 Sar1 同时定位于 ER 出口位点和 ER-Golgi 中间区(ERGIC)区域。此外,受损的胶原蛋白分泌将活化的 Sar1 限制在 ER 出口位点,这意味着 Sar1 通过 ERGIC 激活在胶原蛋白分泌中的重要性。
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引用次数: 0
Permanent deconstruction of intracellular primary cilia in differentiating granule cell neurons. 分化中的颗粒细胞神经元细胞内原始纤毛的永久性解构
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-08-13 DOI: 10.1083/jcb.202404038
Carolyn M Ott, Sandii Constable, Tri M Nguyen, Kevin White, Wei-Chung Allen Lee, Jennifer Lippincott-Schwartz, Saikat Mukhopadhyay

Primary cilia on granule cell neuron progenitors in the developing cerebellum detect sonic hedgehog to facilitate proliferation. Following differentiation, cerebellar granule cells become the most abundant neuronal cell type in the brain. While granule cell cilia are essential during early developmental stages, they become infrequent upon maturation. Here, we provide nanoscopic resolution of cilia in situ using large-scale electron microscopy volumes and immunostaining of mouse cerebella. In many granule cells, we found intracellular cilia, concealed from the external environment. Cilia were disassembled in differentiating granule cell neurons-in a process we call cilia deconstruction-distinct from premitotic cilia resorption in proliferating progenitors. In differentiating granule cells, cilia deconstruction involved unique disassembly intermediates, and, as maturation progressed, mother centriolar docking at the plasma membrane. Unlike ciliated neurons in other brain regions, our results show the deconstruction of concealed cilia in differentiating granule cells, which might prevent mitogenic hedgehog responsiveness. Ciliary deconstruction could be paradigmatic of cilia removal during differentiation in other tissues.

发育中小脑颗粒细胞神经元祖细胞上的初级纤毛能检测到声刺猬,从而促进增殖。分化后,小脑颗粒细胞成为大脑中最丰富的神经细胞类型。虽然颗粒细胞纤毛在早期发育阶段是必不可少的,但在成熟后就变得不常见了。在这里,我们利用大尺寸电子显微镜和小鼠小脑的免疫染色,提供了原位纤毛的纳米分辨率。在许多颗粒细胞中,我们发现了细胞内的纤毛,它们被外部环境所掩盖。在分化的颗粒细胞神经元中,纤毛被分解--我们称这一过程为纤毛解构--有别于增殖祖细胞中的纤毛吸收。在分化的颗粒细胞中,纤毛解构涉及独特的解构中间体,随着成熟的进展,母中心粒在质膜上对接。与其他脑区的纤毛神经元不同,我们的研究结果表明,在分化的颗粒细胞中,隐藏的纤毛被解构,这可能会阻止有丝分裂刺猬的反应性。纤毛解构可能是其他组织分化过程中纤毛去除的范例。
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引用次数: 0
Chemical transformation of the multibudding yeast, Aureobasidium pullulans. 多芽酵母 Aureobasidium pullulans 的化学转化。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-06-27 DOI: 10.1083/jcb.202402114
Alison C E Wirshing, Claudia A Petrucco, Daniel J Lew

Aureobasidium pullulans is a ubiquitous polymorphic black yeast with industrial and agricultural applications. It has recently gained attention amongst cell biologists for its unconventional mode of proliferation in which multinucleate yeast cells make multiple buds within a single cell cycle. Here, we combine a chemical transformation method with genome-targeted homologous recombination to yield ∼60 transformants/μg of DNA in just 3 days. This protocol is simple, inexpensive, and requires no specialized equipment. We also describe vectors with codon-optimized green and red fluorescent proteins for A. pullulans and use these tools to explore novel cell biology. Quantitative imaging of a strain expressing cytosolic and nuclear markers showed that although the nuclear number varies considerably among cells of similar volume, total nuclear volume scales with cell volume over an impressive 70-fold size range. The protocols and tools described here expand the toolkit for A. pullulans biologists and will help researchers address the many other puzzles posed by this polyextremotolerant and morphologically plastic organism.

拉氏酵母菌(Aureobasidium pullulans)是一种普遍存在的多态黑色酵母菌,在工业和农业领域都有应用。最近,它因其非传统的增殖模式(多核酵母细胞在一个细胞周期内产生多个芽)而受到细胞生物学家的关注。在这里,我们将化学转化方法与基因组靶向同源重组相结合,仅用 3 天就能获得 ∼60 个转化子/μg DNA。这种方法简单、廉价,而且不需要专门的设备。我们还描述了带有密码子优化的绿色和红色荧光蛋白的拉氏杆菌载体,并利用这些工具探索新的细胞生物学。对一株表达细胞膜和细胞核标记物的菌株进行定量成像显示,虽然细胞核数量在体积相似的细胞中变化很大,但细胞核的总体积与细胞体积成比例,大小范围达到令人印象深刻的 70 倍。本文描述的方案和工具扩展了 A. pullulans 生物学家的工具包,将帮助研究人员解决这种多极端耐受性和形态可塑性生物带来的许多其他难题。
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引用次数: 0
Murine glial protrusion transcripts predict localized Drosophila glial mRNAs involved in plasticity. 小鼠神经胶质突起转录本预测了果蝇神经胶质 mRNA 的定位,这些 mRNA 与可塑性有关。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-07-22 DOI: 10.1083/jcb.202306152
Jeffrey Y Lee, Dalia S Gala, Maria Kiourlappou, Julia Olivares-Abril, Jana Joha, Joshua S Titlow, Rita O Teodoro, Ilan Davis

The polarization of cells often involves the transport of specific mRNAs and their localized translation in distal projections. Neurons and glia are both known to contain long cytoplasmic processes, while localized transcripts have only been studied extensively in neurons, not glia, especially in intact nervous systems. Here, we predict 1,740 localized Drosophila glial transcripts by extrapolating from our meta-analysis of seven existing studies characterizing the localized transcriptomes and translatomes of synaptically associated mammalian glia. We demonstrate that the localization of mRNAs in mammalian glial projections strongly predicts the localization of their high-confidence Drosophila homologs in larval motor neuron-associated glial projections and are highly statistically enriched for genes associated with neurological diseases. We further show that some of these localized glial transcripts are specifically required in glia for structural plasticity at the nearby neuromuscular junction synapses. We conclude that peripheral glial mRNA localization is a common and conserved phenomenon and propose that it is likely to be functionally important in disease.

细胞的极化往往涉及特定 mRNA 的运输及其在远端突起中的定位翻译。众所周知,神经元和胶质细胞都含有长的细胞质过程,而定位转录本只在神经元中得到了广泛研究,而在胶质细胞中却没有,尤其是在完整的神经系统中。在这里,我们通过对现有的七项研究进行荟萃分析,预测了 1740 个果蝇神经胶质的定位转录本,这些研究描述了与突触相关的哺乳动物神经胶质的定位转录本组和转译组的特征。我们证明,哺乳动物神经胶质突起中 mRNA 的定位强烈预测了其高置信度果蝇同源物在幼虫运动神经元相关神经胶质突起中的定位,并且在统计学上高度富集了与神经系统疾病相关的基因。我们进一步发现,这些定位的神经胶质转录本中有一些是神经胶质对附近神经肌肉接头突触结构可塑性的特异性要求。我们的结论是,外周神经胶质 mRNA 定位是一种常见的保守现象,并认为它在疾病中可能具有重要功能。
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引用次数: 0
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