Semaphorin

信号素
  • 文章类型: Journal Article
    在发育中的神经系统中,在神经回路达到最终的神经支配拓扑结构之前,轴突关节通常会经历复杂的重排。在斑马鱼的侧线感觉系统中,发育中的感觉轴突会重组其末端乔化模式,以在机械感觉毛细胞周围建立精确的神经微电路。然而,对感觉轴形态的变化和微电路组件背后的调节器的定量理解仍然是神秘的。这里,我们报道,Sema7A(Sema7A)是这些过程的重要中介。利用半自动三维神经突追踪方法和计算技术,我们在野生型和Sema7A功能丧失突变体中鉴定并定量分析了形成网络的独特拓扑特征.与野生型动物相比,Sema7A突变体中的感觉轴突显示出异常的树枝状,网络拓扑结构混乱,与毛细胞的接触减少。此外,非毛细胞对Sema7A分泌形式的异位表达诱导感觉轴突的趋化性引导。我们的发现表明,Sema7A可能既可以作为一种近碱,又可以作为一种分泌的线索,以在感觉器官发育过程中对神经回路进行图案化。
    In a developing nervous system, axonal arbors often undergo complex rearrangements before neural circuits attain their final innervation topology. In the lateral line sensory system of the zebrafish, developing sensory axons reorganize their terminal arborization patterns to establish precise neural microcircuits around the mechanosensory hair cells. However, a quantitative understanding of the changes in the sensory arbor morphology and the regulators behind the microcircuit assembly remain enigmatic. Here, we report that Semaphorin7A (Sema7A) acts as an important mediator of these processes. Utilizing a semi-automated three-dimensional neurite tracing methodology and computational techniques, we have identified and quantitatively analyzed distinct topological features that shape the network in wild-type and Sema7A loss-of-function mutants. In contrast to those of wild-type animals, the sensory axons in Sema7A mutants display aberrant arborizations with disorganized network topology and diminished contacts to hair cells. Moreover, ectopic expression of a secreted form of Sema7A by non-hair cells induces chemotropic guidance of sensory axons. Our findings propose that Sema7A likely functions both as a juxtracrine and as a secreted cue to pattern neural circuitry during sensory organ development.
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  • 文章类型: Journal Article
    功能性神经系统的精确组装依赖于轴突引导线索。除了参与它们的同源受体和启动调节细胞骨架动力学的信号级联,引导线索也结合细胞外基质的成分,特别是蛋白聚糖,然而,这些相互作用的作用和机制仍然知之甚少。我们发现果蝇分泌的信号蛋白与蛋白聚糖的糖胺聚糖(GAG)链特异性结合,显示基于硫酸化程度的偏好。Sema2b的结构分析揭示了位于规范丛蛋白结合位点之外的多个GAG结合位点,最高亲和力结合位点位于C末端尾部,其特征是富含赖氨酸的螺旋排列,似乎在分泌的信号蛋白中保守。体内研究揭示了Sema2bC末端尾巴在指定嗅觉受体神经元的轨迹中的关键作用。我们建议分泌的信号蛋白通过与蛋白聚糖的GAG链相互作用而连接到细胞表面,促进它们在传递的轴突上呈现给同源受体。
    The precise assembly of a functional nervous system relies on axon guidance cues. Beyond engaging their cognate receptors and initiating signaling cascades that modulate cytoskeletal dynamics, guidance cues also bind components of the extracellular matrix, notably proteoglycans, yet the role and mechanisms of these interactions remain poorly understood. We found that Drosophila secreted semaphorins bind specifically to glycosaminoglycan (GAG) chains of proteoglycans, showing a preference based on the degree of sulfation. Structural analysis of Sema2b unveiled multiple GAG-binding sites positioned outside canonical plexin-binding site, with the highest affinity binding site located at the C-terminal tail, characterized by a lysine-rich helical arrangement that appears to be conserved across secreted semaphorins. In vivo studies revealed a crucial role of the Sema2b C-terminal tail in specifying the trajectory of olfactory receptor neurons. We propose that secreted semaphorins tether to the cell surface through interactions with GAG chains of proteoglycans, facilitating their presentation to cognate receptors on passing axons.
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  • 文章类型: Journal Article
    对形态发生原信号水平的精确控制对于正常发育至关重要。一个突出的问题是:什么机制确保适当的形态发生活性和正确的细胞反应?以前的工作已经确定了信号素(SEMA)受体,神经菌毛蛋白(NRP)和神经丛蛋白(PLXNs),作为Hedgehog(HH)信号通路的正调节因子。这里,我们提供了NRP和PLXN拮抗成纤维细胞和上皮细胞中Wnt信号的证据.Further,成纤维细胞中的Nrp1/2缺失导致基线Wnt途径活性升高和对Wnt刺激的最大应答增加。值得注意的是,与HH信号相反,SEMA受体介导的Wnt拮抗作用与初级纤毛无关。机械上,PLXN和NRP在Dishevelled(DVL)的下游起作用,以蛋白酶体依赖性方式使β-catenin(CTNNB1)不稳定。Further,NRP,但不是PLXN,以GSK3b/CK1依赖性方式拮抗Wnt信号,提示这些SEMA受体不同的抑制机制。总的来说,这项研究将SEMA受体鉴定为新型Wnt通路拮抗剂,它们也可能在整合来自多个输入的信号方面发挥更大的作用.
    Precise control of morphogen signaling levels is essential for proper development. An outstanding question is: what mechanisms ensure proper morphogen activity and correct cellular responses? Previous work has identified Semaphorin (SEMA) receptors, Neuropilins (NRPs) and Plexins (PLXNs), as positive regulators of the Hedgehog (HH) signaling pathway. Here, we provide evidence that NRPs and PLXNs antagonize Wnt signaling in both fibroblasts and epithelial cells. Further, Nrp1/2 deletion in fibroblasts results in elevated baseline Wnt pathway activity and increased maximal responses to Wnt stimulation. Notably, and in contrast to HH signaling, SEMA receptor-mediated Wnt antagonism is independent of primary cilia. Mechanistically, PLXNs and NRPs act downstream of Dishevelled (DVL) to destabilize β-catenin (CTNNB1) in a proteosome-dependent manner. Further, NRPs, but not PLXNs, act in a GSK3β/CK1-dependent fashion to antagonize Wnt signaling, suggesting distinct repressive mechanisms for these SEMA receptors. Overall, this study identifies SEMA receptors as novel Wnt pathway antagonists that may also play larger roles integrating signals from multiple inputs.
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  • 文章类型: Journal Article
    视觉电路发展的特征是将神经质细分成容纳不同突触连接组的层。我们发现在果蝇髓质中,这种分层的组织取决于轴突指导调节神经丛蛋白A。在丛蛋白A无效突变体中,与对照组相比,髓质神经纤维的突触层和单个神经元的乔化更宽,更少。对信号素功能的分析表明信号素1a,作用于延髓神经元的子集,是髓质夹层中神经丛蛋白A的主要合作伙伴。去除内源性神经丛蛋白A的细胞质结构域对髓质层形成的影响要小得多;然而,丛蛋白A的无效和细胞质结构域缺失突变均导致延髓神经纤维的整体形状改变。这些数据表明神经丛蛋白A作为受体介导髓质神经纤维的形态发生,并作为信号素1a的配体将其细分为各层。它的两个独立功能说明了一些引导分子如何通过各自扮演多个角色来组织复杂的大脑结构。
    Visual circuit development is characterized by subdivision of neuropils into layers that house distinct sets of synaptic connections. We find that, in the Drosophila medulla, this layered organization depends on the axon guidance regulator Plexin A. In Plexin A null mutants, synaptic layers of the medulla neuropil and arborizations of individual neurons are wider and less distinct than in controls. Analysis of semaphorin function indicates that Semaphorin 1a, acting in a subset of medulla neurons, is the primary partner for Plexin A in medulla lamination. Removal of the cytoplasmic domain of endogenous Plexin A has little effect on the formation of medulla layers; however, both null and cytoplasmic domain deletion mutations of Plexin A result in an altered overall shape of the medulla neuropil. These data suggest that Plexin A acts as a receptor to mediate morphogenesis of the medulla neuropil, and as a ligand for Semaphorin 1a to subdivide it into layers. Its two independent functions illustrate how a few guidance molecules can organize complex brain structures by each playing multiple roles.
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  • 文章类型: Journal Article
    背景:缺血性卒中可能通过增殖引发神经可塑性改变,向病变迁移,和神经祖细胞分化为成熟神经元。重复经颅磁刺激(rTMS)可促进脑可塑性。本研究旨在通过给药血浆miRs17~92、Netrin-1、Sema3A、BDNF。
    方法:在本病例对照研究中,我们将19例缺血性卒中患者从症状发作(T0)至神经导航性rTMS或假刺激5天内随机分组.在中风发作的第7天至第14天之间每天对中风半球施加刺激。在第一个rTMS切片(T7)之前,在T0收集血样,并且在最后的rTMS会话结束时(T14)。5名健康对照也被纳入本研究。
    结果:在19例患者中,10接受rTMS和9假刺激。与假手术组相比,在rTMS组中,血浆miRs17〜92和Ntn-1水平显着增加,而Sema3A水平趋于降低。在多元线性回归分析中,在T14时,rTMS与Ntn-1和miR-25水平独立相关。
    结论:我们发现rTMS与神经发生/轴突发生生物标志物增强之间存在关联。我们的初步数据表明,rTMS可能会积极干扰缺血后人脑的自然内源性可塑性现象。
    BACKGROUND: Ischemic stroke may trigger neuroplastic changes via proliferation, migration towards the lesion, and differentiation of neuroprogenitor cells into mature neurons. Repetitive Transcranial Magnetic Stimulation (rTMS) may promote brain plasticity. This study aimed to assess rTMS\'s effect on post-stroke endogenous neuroplasticity by dosing plasma miRs 17~92, Netrin-1, Sema3A, and BDNF.
    METHODS: In this case-controlled study, we randomized 19 ischemic stroke patients within five days from symptoms onset (T0) to neuronavigated-rTMS or sham stimulation. Stimulation was applied on the stroke hemisphere daily between the 7th and 14th day from stroke onset. Blood samples were collected at T0, before the first rTMS section (T7), and at the end of the last rTMS session (T14). Five healthy controls were also enrolled in this study.
    RESULTS: Of 19 patients, 10 received rTMS and 9 sham stimulation. Compared with the sham group, in the rTMS group, plasma levels of miRs17~92 and Ntn-1 significantly increased whereas Sema3A levels tended to decrease. In multivariate linear regression analyses, rTMS was independently related to Ntn-1 and miR-25 levels at T14.
    CONCLUSIONS: We found an association between rTMS and neurogenesis/axonogenesis biomarker enhancement. Our preliminary data suggest that rTMS may positively interfere with natural endogenous plasticity phenomena of the post-ischemic human brain.
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  • 文章类型: Journal Article
    胰腺癌,人类最致命的癌症之一,包括几种非上皮和基质成分,如激活的成纤维细胞,血管细胞,神经细胞和免疫细胞,涉及不同的癌症。血管内皮细胞生长因子165受体1[神经纤毛蛋白-1(NRP-1)]和2(NRP-2)在胰腺癌的生物学行为中起作用,可能是潜在的治疗靶点。NRP蛋白家族作为血管内皮生长因子的共受体,转化生长因子β,肝细胞生长因子,成纤维细胞生长因子,信号素3,表皮生长因子,胰岛素样生长因子和血小板源性生长因子。对涉及NRP蛋白家族的机制的研究可能有助于开发克服胰腺癌治疗耐药性的新方法。本综述旨在深入探讨NRP家族蛋白在胰腺癌中的多方面作用。包括在胰腺腺癌背景下进行的单细胞分析的最新发现,这揭示了NRP蛋白在细胞水平上的复杂参与。通过这些努力,本研究努力进一步揭示它们与不同生物过程的关系,以及它们在各种治疗方式中作为治疗靶点的潜力,为胰腺癌的治疗提供了新的视角和方向。
    Pancreatic cancer, one of the most fatal types of human cancers, includes several non-epithelial and stromal components, such as activated fibroblasts, vascular cells, neural cells and immune cells, that are involved in different cancers. Vascular endothelial cell growth factor 165 receptors 1 [neuropilin-1 (NRP-1)] and 2 (NRP-2) play a role in the biological behaviors of pancreatic cancer and may appear as potential therapeutic targets. The NRP family of proteins serve as co-receptors for vascular endothelial growth factor, transforming growth factor β, hepatocyte growth factor, fibroblast growth factor, semaphorin 3, epidermal growth factor, insulin-like growth factor and platelet-derived growth factor. Investigations of mechanisms that involve the NRP family of proteins may help develop novel approaches for overcoming therapy resistance in pancreatic cancer. The present review aimed to provide an in-depth exploration of the multifaceted roles of the NRP family of proteins in pancreatic cancer, including recent findings from single-cell analysis conducted within the context of pancreatic adenocarcinoma, which revealed the intricate involvement of NRP proteins at the cellular level. Through these efforts, the present study endeavored to further reveal their relationships with different biological processes and their potential as therapeutic targets in various treatment modalities, offering novel perspectives and directions for the treatment of pancreatic cancer.
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  • 文章类型: Journal Article
    卵泡是一个复杂的结构,可以保护和帮助卵母细胞的成熟,然后通过受控的排卵分子和结构重塑过程释放它。孕激素受体(PGR)已被证明在调节排卵相关基因表达变化中至关重要。在这项研究中,我们发现排卵过程中PGR-/-小鼠颗粒细胞中细胞粘附受体基因Sema7A的表达被破坏。我们随后发现,促性腺激素和缺氧促进了Sema7A在排卵前卵泡中的表达,建立一个不对称的模式与SEMA7A蛋白富集在大腔卵泡的顶点。Sema7A表达在排卵期通过PGR依赖性机制下调,SEMA7A蛋白的丰度降低,不对称模式在排卵刺激后变得更加均匀。Sema7A的受体可以排斥或促进细胞间粘附。在排卵期间,排斥性Plxnc1和粘附性Itga5/Itgb1受体的惊人反向调节可能有助于剧烈的组织重塑。在排卵周期颗粒细胞和卵丘-卵母细胞复合物(COCs)中,粘附受体Itga5显着增加,和功能测定表明,围排卵颗粒细胞和COCs获得增加的粘附表型,而Sema7A排斥颗粒细胞接触。这些发现表明,Sema7A及其相关受体的调节,与整合素α5的调节一起,可能对于建立多层卵泡结构以及促进排卵过程中卵丘-卵母细胞复合物的重塑和顶端释放至关重要。
    The ovarian follicle is a complex structure that protects and helps in the maturation of the oocyte, and then releases it through the controlled molecular and structural remodeling process of ovulation. The progesterone receptor (PGR) has been shown to be essential in regulating ovulation-related gene expression changes. In this study, we found disrupted expression of the cellular adhesion receptor gene Sema7A in the granulosa cells of PGR-/- mice during ovulation. We subsequently found that expression of Sema7A in preovulatory follicles is promoted by gonadotropins and hypoxia, establishing an asymmetrical pattern with the SEMA7A protein enriched at the apex of large antral follicles. Sema7A expression was downregulated through a PGR-dependent mechanism in the periovulatory period, the abundance of SEMA7A protein was reduced, and the asymmetric pattern became more homogeneous after an ovulatory stimulus. Receptors for Sema7A can either repel or promote intercellular adhesion. During ovulation, striking inverse regulation of repulsive Plxnc1 and adhesive Itga5/Itgb1 receptors likely contributes to dramatic tissue remodeling. The adhesive receptor Itga5 was significantly increased in periovulatory granulosa cells and cumulus-oocyte complexes (COCs), and functional assays showed that periovulatory granulosa cells and COCs acquire increased adhesive phenotypes, while Sema7A repels granulosa cell contact. These findings suggest that the regulation of Sema7A and its associated receptors, along with the modulation of integrin α5, may be critical in establishing the multilaminar ovarian follicle structure and facilitating the remodeling and apical release of the cumulus-oocyte complex during ovulation.
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  • 文章类型: Journal Article
    信号素家族是一组广泛研究其在神经系统中的功能的蛋白质。它们由八个在脊椎动物中普遍表达的亚家族组成,无脊椎动物,和病毒,以膜结合或分泌形式存在。新出现的证据表明信号在神经系统外的相关性,包括血管生成,心脏发生,破骨细胞生成,肿瘤进展,and,最近,免疫系统。这篇综述提供了有关信号素在免疫系统中的作用的当前知识的广泛概述,特别是它参与炎症和传染病,包括衣原体感染.
    The Semaphorin family is a group of proteins studied broadly for their functions in nervous systems. They consist of eight subfamilies ubiquitously expressed in vertebrates, invertebrates, and viruses and exist in membrane-bound or secreted forms. Emerging evidence indicates the relevance of semaphorins outside the nervous system, including angiogenesis, cardiogenesis, osteoclastogenesis, tumour progression, and, more recently, the immune system. This review provides a broad overview of current knowledge on the role of semaphorins in the immune system, particularly its involvement in inflammatory and infectious diseases, including chlamydial infections.
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  • 文章类型: Journal Article
    轴突成束被认为是神经回路形成和功能的关键步骤。最近的研究揭示了轴突成束形成的各种分子机制;然而,轴突成束的影响,和它的必然结果,蠕动,神经电路布线仍不清楚。感觉运动皮层中的皮质脊髓(CS)神经元将轴突投射到脊髓以控制熟练的运动。在啮齿动物中,轴突在大脑中保持紧密的束状,并穿过脊髓的背侧。在这里,我们显示了plexinA1(PlexA1)和plexinA3(PlexA3)受体由CS神经元表达,而它们的配体,semaphorin-5A(Sema5A)和semaphorin-5B(Sema5B)在CS轴突的截流部位的髓质中表达,以抑制这些轴突的过早蠕动。在没有Sema5A/5B-PlexA1/A3信令的情况下,一些CS轴突在脑干的髓质中过早地萎缩,以及那些在脊髓灰质而不是脊髓背侧筋膜中异常横行的CS轴突。在没有Sema5A/Sema5B-PlexA1/A3信号时,CS轴突,通常会支配腰脊髓,在脊髓灰质中被解开,过早地支配宫颈灰质,而腰椎灰质的神经支配减少。在Sema5A/5B和PlexA1/A3突变小鼠(两种性别)中,异常刺激后肢运动皮层会引起前肢肌肉的强烈激活。最后,Sema5A/5B和PlexA1/A3突变小鼠在熟练运动中表现出缺陷。这些结果表明,适当的神经电路布线需要适当的CS轴突束感,并最终影响进行熟练运动的能力。意义陈述:轴突成束被认为对神经回路的形成和功能至关重要。然而,轴突成束缺陷是否以及如何影响神经回路的形成和功能尚不清楚。在这里,我们检查跨膜蛋白信号量-5A(Sema5A)和信号量-5B(Sema5B),和它们的受体,plexinA1(PlexA1)和plexinA3(PlexA3)在皮质脊髓回路的发育中起作用。我们发现Sema5A/Sema5B和PlexA1/A3是皮质脊髓神经元适当轴突成束所必需的。此外,Sema5A/5B和PlexA1/A3突变小鼠在熟练的运动行为中显示出明显的缺陷。因此,这些结果强烈表明,小鼠皮质脊髓回路的适当形成和功能需要适当的皮质脊髓轴突成束。
    Axon fasciculation is thought to be a critical step in neural circuit formation and function. Recent studies have revealed various molecular mechanisms that underlie axon fasciculation; however, the impacts of axon fasciculation, and its corollary, defasciculation, on neural circuit wiring remain unclear. Corticospinal (CS) neurons in the sensorimotor cortex project axons to the spinal cord to control skilled movements. In rodents, the axons remain tightly fasciculated in the brain and traverse the dorsal funiculus of the spinal cord. Here we show that plexinA1 (PlexA1) and plexinA3 (PlexA3) receptors are expressed by CS neurons, whereas their ligands, semaphorin-5A (Sema5A) and semaphorin-5B (Sema5B) are expressed in the medulla at the decussation site of CS axons to inhibit premature defasciculation of these axons. In the absence of Sema5A/5B-PlexA1/A3 signaling, some CS axons are prematurely defasciculated in the medulla of the brainstem, and those defasciculated CS axons aberrantly transverse in the spinal gray matter instead of the spinal dorsal funiculus. In the absence of Sema5A/Sema5B-PlexA1/A3 signaling, CS axons, which would normally innervate the lumbar spinal cord, are unbundled in the spinal gray matter, and prematurely innervate the cervical gray matter with reduced innervation of the lumbar gray matter. In both Sema5A/5B and PlexA1/A3 mutant mice (both sexes), stimulation of the hindlimb motor cortex aberrantly evokes robust forelimb muscle activation. Finally, Sema5A/5B and PlexA1/A3 mutant mice show deficits in skilled movements. These results suggest that proper fasciculation of CS axons is required for appropriate neural circuit wiring and ultimately affect the ability to perform skilled movements.SIGNIFICANCE STATEMENT Axon fasciculation is believed to be essential for neural circuit formation and function. However, whether and how defects in axon fasciculation affect the formation and function of neural circuits remain unclear. Here we examine whether the transmembrane proteins semaphorin-5A (Sema5A) and semaphorin-5B (Sema5B), and their receptors, plexinA1 (PlexA1) and plexinA3 (PlexA3) play roles in the development of corticospinal circuits. We find that Sema5A/Sema5B and PlexA1/A3 are required for proper axon fasciculation of corticospinal neurons. Furthermore, Sema5A/5B and PlexA1/A3 mutant mice show marked deficits in skilled motor behaviors. Therefore, these results strongly suggest that proper corticospinal axon fasciculation is required for the appropriate formation and functioning of corticospinal circuits in mice.
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  • 文章类型: Journal Article
    信号素和神经丛蛋白形成配体/受体对,其对于从细胞增殖到轴突导向的宽范围的发育过程至关重要。信号素作为信号传导受体和配体的能力产生多种反应。这里,我们描述了Semaphorin-6D(Sema6D)和Plexin-A1在视网膜生成轴突的定位和靶向中的新作用。在Plexin-A1或Sema6D突变小鼠中,视神经束穿过而不是位于背外侧膝状核(dLGN)的边界;一些视网膜轴突在视神经束附近和外侧外翻,而不是蠕动并进入目标区域。我们发现Sema6D和Plexin-A1一起作用,并以剂量依赖的方式,因为异位视网膜投影的数量与Sema6D或Plexin-A1表达水平成比例地改变。此外,使用Sema6D或Plexin-A1shRNA的子宫内视网膜电穿孔,我们发现Sema6D和Plexin-A1都是视网膜神经节细胞(RGCs)轴突定位和靶向所必需的.引人注目的是,非电穿孔的RGC轴突也在束区不一致,表明Sema6D和Plexin-A1可以非细胞自主作用,可能通过轴突-轴突相互作用。这些数据为Sema6D和Plexin-A1在视神经束和dLGN的视网膜轴突组织中的剂量依赖性和非细胞自主作用提供了新的证据。重要声明:在支配他们的中枢神经目标之前,视网膜神经节细胞(RGC)轴突在视神经束中成束,然后在目标区域分支和树干。在缺失引导分子Plexin-A1或Semaphorin-6D时,视神经束在背侧外侧膝状核附近变得杂乱无章,并在其中延伸。此外,一些视网膜轴突在血管内形成异位聚集体。Sema6D和Plexin-A1以剂量依赖性方式一起作为受体-配体对,非细胞自主,产生这种发育异常。这种表型突出了轴突导向分子在束线内聚和目标附近的适当疏解以及目标内的乔伯化中的作用。
    Semaphorins and Plexins form ligand/receptor pairs that are crucial for a wide range of developmental processes from cell proliferation to axon guidance. The ability of semaphorins to act both as signaling receptors and ligands yields a multitude of responses. Here, we describe a novel role for Semaphorin-6D (Sema6D) and Plexin-A1 in the positioning and targeting of retinogeniculate axons. In Plexin-A1 or Sema6D mutant mice of either sex, the optic tract courses through, rather than along, the border of the dorsal lateral geniculate nucleus (dLGN), and some retinal axons ectopically arborize adjacent and lateral to the optic tract rather than defasciculating and entering the target region. We find that Sema6D and Plexin-A1 act together in a dose-dependent manner, as the number of the ectopic retinal projections is altered in proportion to the level of Sema6D or Plexin-A1 expression. Moreover, using retinal in utero electroporation of Sema6D or Plexin-A1 shRNA, we show that Sema6D and Plexin-A1 are both required in retinal ganglion cells for axon positioning and targeting. Strikingly, nonelectroporated retinal ganglion cell axons also mistarget in the tract region, indicating that Sema6D and Plexin-A1 can act non-cell-autonomously, potentially through axon-axon interactions. These data provide novel evidence for a dose-dependent and non-cell-autonomous role for Sema6D and Plexin-A1 in retinal axon organization in the optic tract and dLGN.SIGNIFICANCE STATEMENT Before innervating their central brain targets, retinal ganglion cell axons fasciculate in the optic tract and then branch and arborize in their target areas. Upon deletion of the guidance molecules Plexin-A1 or Semaphorin-6D, the optic tract becomes disorganized near and extends within the dorsal lateral geniculate nucleus. In addition, some retinal axons form ectopic aggregates within the defasciculated tract. Sema6D and Plexin-A1 act together as a receptor-ligand pair in a dose-dependent manner, and non-cell-autonomously, to produce this developmental aberration. Such a phenotype highlights an underappreciated role for axon guidance molecules in tract cohesion and appropriate defasciculation near, and arborization within, targets.
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