scholarly journals Regulation of subcellular dendritic synapse specificity by axon guidance cues

2019 ◽  
Author(s):  
Emily C. Sales ◽  
Emily L. Heckman ◽  
Timothy L. Warren ◽  
Chris Q. Doe
Keyword(s):  
Axon Guidance ◽  
Synapse Formation ◽  
Neural Circuit ◽  
Wild Type ◽  
Synaptic Specificity ◽  
Guidance Cues ◽  
Guidance Receptors ◽  
Subcellular Domains ◽  
Dendritic Arbors ◽  
Lateral Dendrite

AbstractNeural circuit assembly occurs with subcellular precision, yet the mechanisms underlying this precision remain largely unknown. Subcellular synaptic specificity could be achieved by molecularly distinct subcellular domains that locally regulate synapse formation, or by axon guidance cues restricting access to one of several acceptable targets. We address these models using two Drosophila neurons: the dbd sensory neuron and the A08a interneuron. In wild-type larvae, dbd synapses with the A08a medial dendrite but not the A08a lateral dendrite. dbd-specific overexpression of the guidance receptors Unc-5 or Robo-2 results in lateralization of the dbd axon, which forms anatomical and functional monosynaptic connections with the A08a lateral dendrite. We conclude that axon guidance cues, not molecularly distinct dendritic arbors, are a major determinant of dbd-A08a subcellular synapse specificity.

scholarly journals Regulation of subcellular dendritic synapse specificity by axon guidance cues

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Emily C Sales ◽  
Emily L Heckman ◽  
Timothy L Warren ◽  
Chris Q Doe
Keyword(s):  
Axon Guidance ◽  
Synapse Formation ◽  
Neural Circuit ◽  
Wild Type ◽  
Synaptic Specificity ◽  
Guidance Cues ◽  
Guidance Receptors ◽  
Subcellular Domains ◽  
Dendritic Arbors ◽  
Lateral Dendrite

Neural circuit assembly occurs with subcellular precision, yet the mechanisms underlying this precision remain largely unknown. Subcellular synaptic specificity could be achieved by molecularly distinct subcellular domains that locally regulate synapse formation, or by axon guidance cues restricting access to one of several acceptable targets. We address these models using two Drosophila neurons: the dbd sensory neuron and the A08a interneuron. In wild-type larvae, dbd synapses with the A08a medial dendrite but not the A08a lateral dendrite. dbd-specific overexpression of the guidance receptors Unc-5 or Robo-2 results in lateralization of the dbd axon, which forms anatomical and functional monosynaptic connections with the A08a lateral dendrite. We conclude that axon guidance cues, not molecularly distinct dendritic arbors, are a major determinant of dbd-A08a subcellular synapse specificity.

scholarly journals Minimal structural elements required for midline repulsive signaling and regulation of Drosophila Robo1

2020 ◽  
Author(s):  
Haley E. Brown ◽  
Timothy A. Evans
Keyword(s):  
Axon Guidance ◽  
Biochemical Properties ◽  
Structural Elements ◽  
Wild Type ◽  
Domain Interaction ◽  
Robo Receptors ◽  
Guidance Receptors ◽  
Repulsive Signaling

AbstractThe Roundabout (Robo) family of axon guidance receptors has a conserved ectodomain arrangement of five immunoglobulin-like (Ig) domains plus three fibronectin (Fn) repeats. Based on the strong evolutionary conservation of this domain structure among Robo receptors, as well as in vitro structural and domain-domain interaction studies of Robo family members, this ectodomain arrangement is predicted to be important for Robo receptor signaling in response to Slit ligands. Here, we define the minimal ectodomain structure required for Slit binding and midline repulsive signaling in vivo by Drosophila Robo1. We find that the majority of the Robo1 ectodomain is dispensable for both Slit binding and repulsive signaling. We show that a significant level of midline repulsive signaling activity is retained when all Robo1 ectodomain elements apart from Ig1 are deleted, and that the combination of Ig1 plus one additional ectodomain element (Ig2, Ig5, or Fn3) is sufficient to restore midline repulsion to wild type levels. Further, we find that deleting four out of five Robo1 Ig domains (ΔIg2-5) does not affect negative regulation of Robo1 by Commissureless (Comm) or Robo2, while variants lacking all three fibronectin repeats (ΔFn1-3 and ΔIg2-Fn3) are insensitive to regulation by both Comm and Robo2, signifying a novel regulatory role for Robo1’s Fn repeats. Our results provide an in vivo perspective on the importance of the conserved 5+3 ectodomain structure of Robo receptors, and suggest that specific biochemical properties and/or ectodomain structural conformations observed in vitro for domains other than Ig1 may have limited significance for in vivo signaling in the context of midline repulsion.

scholarly journals Where does axon guidance lead us?

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 78 ◽  
Author(s):  
Esther Stoeckli
Keyword(s):  
Axon Guidance ◽  
Protein Interactions ◽  
Neural Circuit ◽  
Surface Expression ◽  
Target Cells ◽  
Protein Protein Interactions ◽  
Guidance Receptors ◽  
Recent Developments ◽  
Genomic Studies ◽  
Circuit Formation

During neural circuit formation, axons need to navigate to their target cells in a complex, constantly changing environment. Although we most likely have identified most axon guidance cues and their receptors, we still cannot explain the molecular background of pathfinding for any subpopulation of axons. We lack mechanistic insight into the regulation of interactions between guidance receptors and their ligands. Recent developments in the field of axon guidance suggest that the regulation of surface expression of guidance receptors comprises transcriptional, translational, and post-translational mechanisms, such as trafficking of vesicles with specific cargos, protein-protein interactions, and specific proteolysis of guidance receptors. Not only axon guidance molecules but also the regulatory mechanisms that control their spatial and temporal expression are involved in synaptogenesis and synaptic plasticity. Therefore, it is not surprising that genes associated with axon guidance are frequently found in genetic and genomic studies of neurodevelopmental disorders.

scholarly journals Sugar Antennae for Guidance Signals: Syndecans and Glypicans Integrate Directional Cues for Navigating Neurons

2006 ◽  
Vol 6 ◽  
pp. 1024-1036 ◽  
Author(s):  
Christa Rhiner ◽  
Michael O. Hengartner
Keyword(s):  
Cell Surface ◽  
Axon Guidance ◽  
Neuronal Network ◽  
Neuronal Migration ◽  
Synapse Formation ◽  
Nerve Cells ◽  
Heparan Sulfate Proteoglycans ◽  
Vast Number ◽  
Guidance Cues

Attractive and repulsive signals guide migrating nerve cells in all directions when the nervous system starts to form. The neurons extend thin processes, axons, that connect over wide distances with other brain cells to form a complicated neuronal network. One of the most fascinating questions in neuroscience is how the correct wiring of billions of nerve cells in our brain is controlled. Several protein families are known to serve as guidance cues for navigating neurons and axons. Nevertheless, the combinatorial potential of these proteins seems to be insufficient to sculpt the entire neuronal network and the appropriate formation of connections. Recently, heparan sulfate proteoglycans (HSPGs), which are present on the cell surface of neurons and in the extracellular matrix through which neurons and axons migrate, have been found to play a role in regulating cell migration and axon guidance. Intriguingly, the large number of distinct modifications that can be put onto the sugar side chains of these PGs would in principle allow for an enormous diversity of HSPGs, which could help in regulating the vast number of guidance choices taken by individual neurons. In this review, we will focus on the role of the cell surface HSPGs syndecan and glypican and specific HS modifications in promoting neuronal migration, axon guidance, and synapse formation.

The homeodomain protein Vax2 patterns the dorsoventral and nasotemporal axes of the eye

Development ◽  
2002 ◽  
Vol 129 (3) ◽  
pp. 797-804 ◽  
Author(s):  
Stina H. Mui ◽  
Robert Hindges ◽  
Dennis D. M. O’Leary ◽  
Greg Lemke ◽  
Stefano Bertuzzi
Keyword(s):  
Superior Colliculus ◽  
Axon Guidance ◽  
Transcriptional Regulators ◽  
Topographic Mapping ◽  
Homeodomain Protein ◽  
Wild Type ◽  
Guidance Cues ◽  
Axonal Connections ◽  
Mammalian Retina ◽  
Axial Polarization

The vertebrate retina is highly ordered along both its dorsoventral (DV) and nasotemporal (NT) axes, and this order is topographically maintained in its axonal connections to the superior colliculus of the midbrain. Although the graded axon guidance cues that mediate the topographic mapping of retinocollicular connections are increasingly well understood, the transcriptional regulators that set the DV and NT gradients of these cues are not. We now provide genetic evidence that Vax2, a homeodomain protein expressed in the ventral retina, is one such regulator. We demonstrate that in Vax2 mutant mice, retinocollicular projections from the ventral temporal retina are dorsalized relative to wild type. Remarkably, however, this dorsalization becomes systematically less severe in progressively more nasal regions of the ventral retina. Vax2 mutants also exhibit flattened DV and NT gradients of the EphA5, EphB2, EphB3, ephrin-B1 and ephrin-B2 axon guidance cues. Together, these data identify Vax2 as a fundamental regulator of axial polarization in the mammalian retina.

scholarly journals Synaptogenic activity of the axon guidance molecule Robo2 is critical for hippocampal circuit function

2019 ◽  
Author(s):  
Heike Blockus ◽  
Sebastian V. Rolotti ◽  
Miklos Szoboszlay ◽  
Tiffany Ming ◽  
Anna Schroeder ◽  
...  
Keyword(s):  
Axon Guidance ◽  
Pyramidal Neurons ◽  
Synapse Formation ◽  
Molecular Level ◽  
Spatial Coding ◽  
Synaptic Specificity ◽  
Circuit Function ◽  
Axon Guidance Molecule ◽  
Guidance Molecule

The developmental transition between axon guidance and synapse formation is critical for circuit assembly but still poorly understood at the molecular level. We hypothesized that this key transition could be regulated by axon guidance cues switching their function to regulate synaptogenesis with subcellular specificity. Here, we report evidence for such a functional switch, describing a novel role for the axon guidance molecule Robo2 in excitatory synapse formation onto dendrites of CA1 pyramidal neurons (PNs) in the mouse hippocampus. Cell-autonomous deletion of Robo2 from CA1 PNs leads to a drastic reduction of the number of excitatory synapses specifically in proximal dendritic compartments. At the molecular level, we show that this novel postsynaptic function of Robo2 depends on both its canonical ligand Slit and a novel interaction with presynaptic Neurexins. Biophysical analysis reveals that Robo2 binds directly to Neurexins via its Ig4-5 domains. In vivo 2-photon Ca2+ imaging of CA1 PNs during spatial navigation in mice shows that sparse deletion of Robo2 during development drastically reduces the likelihood of place cell emergence and alters spatial coding properties of the remaining place cells. Our results identify Robo2 as a novel molecular effector linking synaptic specificity to the acquisition of spatial coding properties characterizing hippocampal circuits.

scholarly journals Syndecan Affects Odor Response as well as Learning and Memory in Drosophila melanogaster

2018 ◽  
Vol 15 (1) ◽  
Author(s):  
Dena Arizanovska ◽  
Jonathan King ◽  
Karl Johnson
Keyword(s):  
Drosophila Melanogaster ◽  
Associative Learning ◽  
Axon Guidance ◽  
Learning And Memory ◽  
Crucial Role ◽  
Synapse Formation ◽  
Sulfate Proteoglycan ◽  
Cns Development ◽  
Wild Type ◽  
Odor Preference

Syndecan (Sdc) is a transmembrane heparan sulfate proteoglycan that plays a crucial role in axon guidance and synapse formation during CNS development in Drosophila melanogaster. To further examine the effect of syndecan on CNS function, Sdc23 mutant D. melanogaster larvae were used to examine odor preference and the capacity for learning and memory. A series of olfaction assays in both wild type and mutant larvae were performed to characterize naive odor responses before adding a training period to identify the capacity for associative learning. These results showed that Sdc23 larvae prefer odors that wild type larvae do not respond to, suggesting a difference in odor receptor pathways and wiring. In addition, associative learning has been documented in wild type larvae, yet no evidence of associative learning in Sdc23 larvae was found, suggesting that the syndecan also plays a role in learning and memory in D. melanogaster larvae. KEYWORDS: Syndecan; Proteoglycans; Neurodevelopment; Axon Guidance; Olfaction; Attraction Index; Associative Learning; Drosophila

scholarly journals Glycosylation in Axonal Guidance

2021 ◽  
Vol 22 (10) ◽  
pp. 5143
Author(s):  
Sampada P. Mutalik ◽  
Stephanie L. Gupton
Keyword(s):  
Neuronal Development ◽  
Axonal Guidance ◽  
Axonal Outgrowth ◽  
Axonal Pathfinding ◽  
Guidance Cues ◽  
Functional Implications ◽  
Protein Functions ◽  
Guidance Receptors ◽  
Surface Localization

How millions of axons navigate accurately toward synaptic targets during development is a long-standing question. Over decades, multiple studies have enriched our understanding of axonal pathfinding with discoveries of guidance molecules and morphogens, their receptors, and downstream signalling mechanisms. Interestingly, classification of attractive and repulsive cues can be fluid, as single guidance cues can act as both. Similarly, guidance cues can be secreted, chemotactic cues or anchored, adhesive cues. How a limited set of guidance cues generate the diversity of axonal guidance responses is not completely understood. Differential expression and surface localization of receptors, as well as crosstalk and spatiotemporal patterning of guidance cues, are extensively studied mechanisms that diversify axon guidance pathways. Posttranslational modification is a common, yet understudied mechanism of diversifying protein functions. Many proteins in axonal guidance pathways are glycoproteins and how glycosylation modulates their function to regulate axonal motility and guidance is an emerging field. In this review, we discuss major classes of glycosylation and their functions in axonal pathfinding. The glycosylation of guidance cues and guidance receptors and their functional implications in axonal outgrowth and pathfinding are discussed. New insights into current challenges and future perspectives of glycosylation pathways in neuronal development are discussed.

Identification Of A Novel Gene Altered In The RQ1 Mutant Strain Affecting Motor Axon Migration In Caenorhabditis Elegans

2021 ◽  
Author(s):  
Haider Z. Naqvi
Keyword(s):  
Caenorhabditis Elegans ◽  
Axon Guidance ◽  
Motor Neurons ◽  
Genetic Background ◽  
Germ Line ◽  
Strong Indication ◽  
Wild Type ◽  
C Elegans ◽  
Novel Gene ◽  
Mutation Region

Novel genetic enhancer screens were conducted targeting mutants involved in the guidance of axons of the DA and DB classes of motor neurons in C. elegans. These mutations are expected in genes that function in parallel to the unc-g/Netrin pathway. The screen was conducted in an unc-5(e53) genetic background and enhancers of the axon guidance defects caused by the absence of UNC-5 were identified. Three mutants were previously identified in the screen called rq1, rq2 and rq3 and two additional mutants called H2-4 and M1-3, were isolated in this study. In order to identify the gene affected by the rq1 mutation, wild-type copies of genes in the mapped rq1 mutation region were injected into the mutants to rescue the phenotypic defects. This is a strong indication that the gene of interest is a novel gene called H04D03.1. Promising results indicate that the H04D03.1 protein also works in germ-line apoptosis.

Development of synapses between identified sensory neurones and giant interneurones in the cockroach Periplaneta americana

Development ◽  
1985 ◽  
Vol 86 (1) ◽  
pp. 227-246
Author(s):  
J. M. Blagburn ◽  
D. J. Beadle ◽  
D. B. Sattelle
Keyword(s):  
Periplaneta Americana ◽  
Synapse Formation ◽  
Primary Dendrite ◽  
Lateral Side ◽  
Synaptic Density ◽  
Sensory Neurones ◽  
Guidance Cues ◽  
First Instar ◽  
Sensory Processes ◽  
Giant Interneurone

The cereal afferent, giant interneurone pathway in Periplaneta americana was used as a model for synapse formation. The morphology of the two identified filiform hair sensory neurones (FHSNs) and of two giant interneurones (GI2 and GI3) was followed throughout embryogenesis by cobalt injection. The FHSN axons enter the CNS at the 45 % stage of embryogenesis, branch at 50 % and form complete arborizations by 70 %. The giant interneurones send out a primary dendrite at 45 %. Secondary branches form between 50 % and 60 % and elaboration of the branching pattern takes place until 80 % embryogenesis. At early stages the FHSN axons are within filopodial range of GI dendrites which may use these sensory processes as guidance cues. Synapse formation between the main FHSN axon shafts and GI dendrites was investigated by injection of the latter with HRP. From 55 % to 65 % the process is initiated by desmosome—like filopodial contacts, with subsequent vesicle clustering and formation of a small synaptic density. Numbers of contacts did not significantly increase after about 70 %, but the number of synapses doubled between 65 % and 75 %, with each GI process becoming postsynaptic to two FHSN synapses and the presynaptic densities lengthening to become bars. From 75 % embryogenesis to hatching there is a further small increase in synaptic bar length. In the first instar GI3 is postsynaptic to both FHSN axons, whereas GI2 forms very few synapses with the axon of the lateral FHSN (LFHSN). This imbalance of contacts is present throughout synaptogenesis, apart from some early filopodial contacts. GI3 forms synapses with the lateral side of the LFHSN axon from 60 % embryogenesis but these are totally absent at hatching. The growth of glia along this side of the axon during the last 30 % of development appears to be associated with degeneration of synapses in this region. Thus, as the dendrites of the GIs grow to form a miniature version of the adult without loss of branches, there is little evidence of an initial overproduction of FHSN—GI synapses. Similarly there is no evidence that GI2 forms ‘incorrect’ synapses with the axon of LFHSN. However, GI3 contacts are removed from an inappropriate region of a correct synaptic partner, LFHSN.

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