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1.
Alternative splicing of the Drosophila gene Dscam results in up to 38,016 different receptor isoforms proposed to interact by isoform-specific homophilic binding. We report that Dscam controls cell-intrinsic aspects of dendrite guidance in all four classes of dendrite arborization (da) neurons. Loss of Dscam in single neurons causes a strong increase in self-crossing. Restriction of dendritic fields of neighboring class III neurons appeared intact in mutant neurons, suggesting that dendritic self-avoidance, but not heteroneuronal tiling, may depend on Dscam. Overexpression of the same Dscam isoforms in two da neurons with overlapping dendritic fields forced a spatial segregation of the two fields, supporting the model that dendritic branches of da neurons use isoform-specific homophilic interactions to ensure minimal overlap. Homophilic binding of the highly diverse extracellular domains of Dscam may therefore limit the use of the same "core" repulsion mechanism to cell-intrinsic interactions without interfering with heteroneuronal interactions. 相似文献
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Dendrite self-avoidance is controlled by Dscam 总被引:6,自引:0,他引:6
Matthews BJ Kim ME Flanagan JJ Hattori D Clemens JC Zipursky SL Grueber WB 《Cell》2007,129(3):593-604
Dendrites distinguish between sister branches and those of other cells. Self-recognition can often lead to repulsion, a process termed "self-avoidance." Here we demonstrate that dendrite self-avoidance in Drosophila da sensory neurons requires cell-recognition molecules encoded by the Dscam locus. By alternative splicing, Dscam encodes a vast number of cell-surface proteins of the immunoglobulin superfamily. We demonstrate that interactions between identical Dscam isoforms on the cell surface underlie self-recognition, while the cytoplasmic tail converts this recognition to dendrite repulsion. Sister dendrites expressing the same isoforms engage in homophilic repulsion. By contrast, Dscam diversity ensures that inappropriate repulsive interactions between dendrites sharing the same receptive field do not occur. The selectivity of Dscam-mediated cell interactions is likely to be widely important in the developing fly nervous system, where processes of cells must distinguish between self and nonself during the construction of neural circuits. 相似文献
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Dendrites of the same neuron usually avoid each other. Some neurons also repel similar neurons through dendrite-dendrite interaction to tile the receptive field. Nonoverlapping coverage based on such contact-dependent repulsion requires dendrites to compete for limited space. Here we show that Drosophila class IV dendritic arborization (da) neurons, which tile the larval body wall, grow their dendrites mainly in a 2D space on the extracellular matrix (ECM) secreted by the epidermis. Removing neuronal integrins or blocking epidermal laminin production causes dendrites to grow into the epidermis, suggesting that integrin-laminin interaction attaches dendrites to the ECM. We further show that some of the previously identified tiling mutants fail to confine dendrites in a 2D plane. Expansion of these mutant dendrites in three dimensions results in overlap of dendritic fields. Moreover, overexpression of integrins in these mutant neurons effectively reduces dendritic crossing and restores tiling, revealing an additional mechanism for tiling. 相似文献
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The target of rapamycin complex 2 controls dendritic tiling of Drosophila sensory neurons through the Tricornered kinase signalling pathway
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Makiko Koike‐Kumagai Kei‐ichiro Yasunaga Rei Morikawa Takahiro Kanamori Kazuo Emoto 《The EMBO journal》2009,28(24):3879-3892
To cover the receptive field completely and non‐redundantly, neurons of certain functional groups arrange tiling of their dendrites. In Drosophila class IV dendrite arborization (da) neurons, the NDR family kinase Tricornered (Trc) is required for homotypic repulsion of dendrites that facilitates dendritic tiling. We here report that Sin1, Rictor, and target of rapamycin (TOR), components of the TOR complex 2 (TORC2), are required for dendritic tiling of class IV da neurons. Similar to trc mutants, dendrites of sin1 and rictor mutants show inappropriate overlap of the dendritic fields. TORC2 components physically and genetically interact with Trc, consistent with a shared role in regulating dendritic tiling. Moreover, TORC2 is essential for Trc phosphorylation on a residue that is critical for Trc activity in vivo and in vitro. Remarkably, neuronal expression of a dominant active form of Trc rescues the tiling defects in sin1 and rictor mutants. These findings suggest that TORC2 likely acts together with the Trc signalling pathway to regulate the dendritic tiling of class IV da neurons, and thus uncover the first neuronal function of TORC2 in vivo. 相似文献
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Dendrites and axons show precise targeting and spacing patterns for proper reception and transmission of information in the nervous system. Self-avoidance promotes complete territory coverage and nonoverlapping spacing between processes from the same cell [1, 2]. Neurons that lack Drosophila Down syndrome cell adhesion molecule 1 (Dscam1) show aberrant overlap, fasciculation, and accumulation of dendrites and axons, demonstrating a role in self-recognition and repulsion leading to self-avoidance [3-11]. Fasciculation and accumulation of processes suggested that Dscam1 might promote process spacing by counterbalancing developmental signals that otherwise promote self-association [9, 12]. Here we show that Dscam1 functions to counter Drosophila sensory neuron dendritic targeting signals provided by secreted Netrin-B and Frazzled, a netrin receptor. Loss of Dscam1 function resulted in aberrant dendrite accumulation at a Netrin-B-expressing target, whereas concomitant loss of Frazzled prevented accumulation and caused severe deficits in dendritic territory coverage. Netrin misexpression was sufficient to induce ectopic dendritic targeting in a Frazzled-dependent manner, whereas Dscam1 was required to prevent ectopic accumulation, consistent with separable roles for these receptors. Our results suggest that Dscam1-mediated self-avoidance counters extrinsic signals that are required for normal dendritic patterning, but whose action would otherwise favor neurite accumulation. Counterbalancing roles for Dscam1 may be deployed in diverse contexts during neural circuit formation. 相似文献
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Insect dendritic arborization (da) neurons provide an opportunity to examine how diverse dendrite morphologies and dendritic territories are established during development. We have examined the morphologies of Drosophila da neurons by using the MARCM (mosaic analysis with a repressible cell marker) system. We show that each of the 15 neurons per abdominal hemisegment spread dendrites to characteristic regions of the epidermis. We place these neurons into four distinct morphological classes distinguished primarily by their dendrite branching complexities. Some class assignments correlate with known proneural gene requirements as well as with central axonal projections. Our data indicate that cells within two morphological classes partition the body wall into distinct, non-overlapping territorial domains and thus are organized as separate tiled sensory systems. The dendritic domains of cells in different classes, by contrast, can overlap extensively. We have examined the cell-autonomous roles of starry night (stan) (also known as flamingo (fmi)) and sequoia (seq) in tiling. Neurons with these genes mutated generally terminate their dendritic fields at normal locations at the lateral margin and segment border, where they meet or approach the like dendrites of adjacent neurons. However, stan mutant neurons occasionally send sparsely branched processes beyond these territories that could potentially mix with adjacent like dendrites. Together, our data suggest that widespread tiling of the larval body wall involves interactions between growing dendritic processes and as yet unidentified signals that allow avoidance by like dendrites. 相似文献
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BACKGROUND: Understanding how dendrites establish their territory is central to elucidating how neuronal circuits are built. Signaling between dendrites is thought to be important for defining their territories; however, the strategies by which different types of dendrites communicate are poorly understood. We have shown previously that two classes of Drosophila peripheral da sensory neurons, the class III and class IV neurons, provide complete and independent tiling of the body wall. By contrast, dendrites of class I and class II neurons do not completely tile the body wall, but they nevertheless occupy nonoverlapping territories. RESULTS: By developing reagents to permit high-resolution studies of dendritic tiling in living animals, we demonstrate that isoneuronal and heteroneuronal class IV dendrites engage in persistent repulsive interactions. In contrast to the extensive dendritic exclusion shown by class IV neurons, duplicated class III neurons showed repulsion only at their dendritic terminals. Supernumerary class I and class II neurons innervated completely overlapping regions of the body wall, and this finding suggests a lack of like-repels-like behavior. CONCLUSIONS: These data suggest that repulsive interactions operate between morphologically alike dendritic arbors in Drosophila. Further, Drosophila da sensory neurons appear to exhibit at least three different types of class-specific dendrite-dendrite interactions: persistent repulsion by all branches, repulsion only by terminal dendrites, and no repulsion. 相似文献
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Recent studies have uncovered the molecular basis of self-avoidance and tiling, two fundamental principles required for the formation of neural circuits. Both of these wiring strategies are established through homophilic repulsion between Dscam proteins expressed on opposing cell surfaces. In Drosophila, Dscam1 mediates self-avoidance, whereas Dscam2 mediates tiling. By contrast, phenotypes in the retina of the DSCAM mutant mouse indicate that DSCAM functions in both self-avoidance and tiling. These findings suggest that homophilic recognition molecules that have classically been defined as adhesive may also function as repulsive cues and that Dscam proteins specialize in this function. 相似文献
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Dscam1 potentially encodes 19,008 ectodomains of a cell recognition molecule of the immunoglobulin (Ig) superfamily through alternative splicing. Each ectodomain, comprising a unique combination of three variable (Ig) domains, exhibits isoform-specific homophilic binding in?vitro. Although we have proposed that the ability of Dscam1 isoforms to distinguish between one another is crucial for neural circuit assembly, via a process called self-avoidance, whether recognition specificity is essential in?vivo has not been addressed. Here we tackle this issue by assessing the function of Dscam1 isoforms with altered binding specificities. We generated pairs of chimeric isoforms that bind to each other (heterophilic) but not to themselves (homophilic). These isoforms failed to support self-avoidance or did so poorly. By contrast, coexpression of complementary isoforms within the same neuron restored self-avoidance. These data establish that recognition between Dscam1 isoforms on neurites of the same cell provides the molecular basis for self-avoidance. 相似文献
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Neurons develop mutually exclusive dendritic domains through self-avoidance and tiling mechanisms. Two recent studies establish that this process is dependent on the restriction of dendrites to a two-dimensional plane through interactions with the extracellular matrix. 相似文献
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To cover the receptive field completely but without redundancy, neurons of certain functional groups exhibit tiling of their dendrites via dendritic repulsion. Here we show that two evolutionarily conserved proteins, the Tricornered (Trc) kinase and Furry (Fry), are essential for tiling and branching control of Drosophila sensory neuron dendrites. Dendrites of fry and trc mutants display excessive terminal branching and fail to avoid homologous dendritic branches, resulting in significant overlap of the dendritic fields. Trc control of dendritic branching involves regulation of RacGTPase, a pathway distinct from the action of Trc in tiling. Timelapse analysis further reveals a specific loss of the ability of growing dendrites to turn away from nearby dendritic branches in fry mutants, suggestive of a defect in like-repels-like avoidance. Thus, the Trc/Fry signaling pathway plays a key role in patterning dendritic fields by promoting avoidance between homologous dendrites as well as by limiting dendritic branching. 相似文献
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Morphological diversity of dendrites contributes to specialized functions of individual neurons. In the present study, we examined the molecular basis that generates distinct morphological classes of Drosophila dendritic arborization (da) neurons. da neurons are classified into classes I to IV in order of increasing territory size and/or branching complexity. We found that Abrupt (Ab), a BTB-zinc finger protein, is expressed selectively in class I cells. Misexpression of ab in neurons of other classes directed them to take the appearance of cells with smaller and/or less elaborated arbors. Loss of ab functions in class I neurons resulted in malformation of their typical comb-like arbor patterns and generation of supernumerary branch terminals. Together with the results of monitoring dendritic dynamics of ab-misexpressing cells or ab mutant ones, all of the data suggested that Ab endows characteristics of dendritic morphogenesis of the class I neurons. 相似文献
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Neurons elaborate dendrites with stereotypic branching patterns, thereby defining their receptive fields. These branching patterns may arise from properties intrinsic to the neurons or competition between neighboring neurons. Genetic and laser ablation studies reported here reveal that different multiple dendritic neurons in the same dorsal cluster in the Drosophila embryonic PNS do not compete with one another for dendritic fields. In contrast, when dendrites from homologous neurons in the two hemisegments meet at the dorsal midline in larval stages, they appear to repel each other. The formation of normal dendritic fields and the competition between dendrites of homologous neurons require the proper expression level of Flamingo, a G protein-coupled receptor-like protein, in embryonic neurons. Whereas Flamingo functions downstream of Frizzled in specifying planar polarity, Flamingo-dependent dendritic outgrowth is independent of Frizzled. 相似文献
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Analysis of Dscam diversity in regulating axon guidance in Drosophila mushroom bodies 总被引:8,自引:0,他引:8
Zhan XL Clemens JC Neves G Hattori D Flanagan JJ Hummel T Vasconcelos ML Chess A Zipursky SL 《Neuron》2004,43(5):673-686
Dscam is an immunoglobulin (Ig) superfamily member that regulates axon guidance and targeting in Drosophila. Alternative splicing potentially generates 38,016 isoforms differing in their extracellular Ig and transmembrane domains. We demonstrate that Dscam mediates the sorting of axons in the developing mushroom body (MB). This correlates with the precise spatiotemporal pattern of Dscam protein expression. We demonstrate that MB neurons express different arrays of Dscam isoforms and that single MB neurons express multiple isoforms. Two different Dscam isoforms differing in their extracellular domains introduced as transgenes into single mutant cells partially rescued the mutant phenotype. Expression of one isoform of Dscam in a cohort of MB neurons induced dominant phenotypes, while expression of a single isoform in a single cell did not. We propose that different extracellular domains of Dscam share a common function and that differences in isoforms expressed on the surface of neighboring axons influence interactions between them. 相似文献
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Dendrites achieve characteristic spacing patterns during development to ensure appropriate coverage of territories. Mechanisms of dendrite positioning via?repulsive dendrite-dendrite interactions are beginning to be elucidated, but the control, and importance, of dendrite positioning relative to their substrate is poorly understood. We found that dendritic branches of Drosophila dendritic arborization sensory neurons can be positioned either at the basal surface of epidermal cells, or enclosed within epidermal invaginations. We show that integrins control dendrite positioning on or within the epidermis in a cell autonomous manner by promoting dendritic retention on the basal surface. Loss of integrin function in neurons resulted in excessive self-crossing and dendrite maintenance defects, the former indicating a role for substrate interactions in self-avoidance. In contrast to a contact-mediated mechanism, we find that integrins prevent crossings that are noncontacting between dendrites in different three-dimensional positions, revealing a requirement?for combined dendrite-dendrite and dendrite-substrate interactions in self-avoidance. 相似文献
17.
Background
Many membrane proteins, including Drosophila Dscam, are enriched in dendrites or axons within neurons. However, little is known about how the differential distribution is established and maintained.Methodology/Principal Findings
Here we investigated the mechanisms underlying the dendritic targeting of Dscam[TM1]. Through forward genetic mosaic screens and by silencing specific genes via targeted RNAi, we found that several genes, encoding various components of the dynein-dynactin complex, are required for restricting Dscam[TM1] to the mushroom body dendrites. In contrast, compromising dynein/dynactin function did not affect dendritic targeting of two other dendritic markers, Nod and Rdl. Tracing newly synthesized Dscam[TM1] further revealed that compromising dynein/dynactin function did not affect the initial dendritic targeting of Dscam[TM1], but disrupted the maintenance of its restriction to dendrites.Conclusions/Significance
The results of this study suggest multiple mechanisms of dendritic protein targeting. Notably, dynein-dynactin plays a role in excluding dendritic Dscam, but not Rdl, from axons by retrograde transport. 相似文献18.
To cover the entire sensory field once and only once, dendrites of some sensory system neurons avoid crossing other dendrites from the same type of neurons. In this issue of Cell, provide first insight into the molecular mechanisms of dendritic tiling. 相似文献
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The Drosophila Dscams are immunoglobulin superfamily members produced from a single gene that is diversified by alternative splicing to produce a family of cell-surface proteins with over 19,000 different ectodomain isoforms. Dscams are critical for neuronal wiring, and mounting evidence suggests that they play a key role in self-avoidance between sister branches from neurons, which depends on homophilic self-recognition by Dscams. Two recent papers shed new light on Dscam recognition: first by showing that the vast majority of Dscam isoforms mediate specific homophilic binding and second by revealing the essence of the molecular basis of homophilic recognition by Dscams through high-resolution structural studies. 相似文献
20.
Precise patterns of motor neuron connectivity depend on the proper establishment and positioning of the dendritic arbor. However, how different motor neurons orient their dendrites to selectively establish synaptic connectivity is not well understood. The Drosophila neuromuscular system provides a simple model to investigate the underlying organizational principles by which distinct subclasses of motor neurons orient their dendrites within the central neuropil. Here we used genetic mosaic techniques to characterize the diverse dendritic morphologies of individual motor neurons from five main nerve branches (ISN, ISNb, ISNd, SNa, and SNc) in the Drosophila larva. We found that motor neurons from different nerve branches project their dendrites to largely stereotyped mediolateral domains in the dorsal region of the neuropil providing full coverage of the receptive territory. Furthermore, dendrites from different motor neurons overlap extensively, regardless of subclass, suggesting that repulsive dendrite-dendrite interactions between motor neurons do not influence the mediolateral positioning of dendritic fields. The anatomical data in this study provide important information regarding how different subclasses of motor neurons organize their dendrites and establishes a foundation for the investigation of the mechanisms that control synaptic connectivity in the Drosophila motor circuit. 相似文献