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The spinal cord receives, relays and processes sensory information from the periphery and integrates this information with descending inputs from supraspinal centres to elicit precise and appropriate behavioural responses and orchestrate body movements. Understanding how the spinal cord circuits that achieve this integration are wired during development is the focus of much research interest. Several families of proteins have well-established roles in guiding developing spinal cord axons, and recent findings have identified new axon guidance molecules. Nevertheless, an integrated view of spinal cord network development is lacking, and many current models have neglected the cellular and functional diversity of spinal cord circuits. Recent advances challenge the existing spinal cord axon guidance dogmas and have provided a more complex, but more faithful, picture of the ontogenesis of vertebrate spinal cord circuits.Spinal neural circuits are established through the navigation of multiple types of neuronal axon to their appropriate synaptic targets. Chédotal reviews the cellular and molecular mechanisms that control this complex wiring, incorporating recent discoveries of new guidance factors.

Intra-retinal axon guidance involves a coordinated expression of transcription factors, axon guidance genes, and secretory molecules within the retina. Pax6, the master regulator gene, has a spatio-temporal expression typically restricted till neurogenesis and fate-specification. However, our observation of persistent expression of Pax6 in mature RGCs led us to hypothesize that Pax6 could play a major role in axon guidance after fate specification. Here, we found significant alteration in intra-retinal axon guidance and fasciculation upon knocking out of Pax6 in E15.5 retina. Through unbiased transcriptome profiling between Pax6 fl/fl and Pax6 −/− retinas, we revealed the mechanistic insight of its role in axon guidance. Our results showed a significant increase in the expression of extracellular matrix molecules and decreased expression of retinal fate specification and neuron projection guidance molecules. Additionally, we found that EphB1 and Sema5B are directly regulated by Pax6 owing to the guidance defects and improper fasciculation of axons. We conclude that Pax6 expression post fate specification of RGCs is necessary for regulating the expression of axon guidance genes and most importantly for maintaining a conducive ECM through which the nascent axons get guided and fasciculate to reach the optic disc.

Glial spatial organization is critical for neural repair after spinal cord injury (SCI). In response to injury, reactive astrocytes extend hypertrophic processes to corral the lesion core and sequester debris and inflammatory cells. How these long, arborized processes remain intact, and how astrocytes avoid collisions to assemble a glial bridge to guide axon pathfinding across lesion site remains unclear. Here we identify the guidance receptor Plexin‑B1 as a regulator of membrane integrity, process plasticity, and astrocyte alignment. Live‑cell imaging reveal that Plexin‑B1 deletion triggers membrane shedding and slows extension and retraction of astrocytic processes. The loss of astrocyte agility disrupts contact‑dependent avoidance, leading to disorganized astrocytes and misguided axons in vitro and in vivo. Mice with astrocyte‑specific Plexin‑B1 deletion show defective glial border, enlarged lesions, inflammatory spill‑over, and dysregulated astrocyte–microglia signaling. These defects result in impaired axon regeneration and poorer functional recovery after spinal‑cord injury. Thus, Plexin‑B1-mediated agility of astrocyte processes safeguards membrane integrity and spatial alignment, enabling effective wound corralling and axon pathfinding during neural repair following SCI. Effective neural repair after spinal cord injury requires alignment of astrocytes to contain the lesion, but the molecular mechanisms that orchestrate glial cell arrangement in injury response are poorly defined. Here, the authors identify guidance receptor Plexin-B1 as a regulator of astrocyte membrane integrity and process plasticity, promoting glial border formation, wound corralling, and functional recovery.

In the developing brain, groups of neurons organize into functional circuits that direct diverse behaviors. One such behavior is the evolutionarily conserved acoustic startle response, which in zebrafish is mediated by a well-defined hindbrain circuit. While numerous molecular pathways that guide neurons to their synaptic partners have been identified, it is unclear if and to what extent distinct neuron populations in the startle circuit utilize shared molecular pathways to ensure coordinated development. Here, we show that the planar cell polarity (PCP)-associated atypical cadherins Celsr3 and Celsr2, as well as the Celsr binding partner Frizzled 3a/Fzd3a, are critical for axon guidance of two neuron types that form synapses with each other: the command-like neuron Mauthner cells that drive the acoustic startle escape response, and spiral fiber neurons which provide excitatory input to Mauthner cells. We find that Mauthner axon growth towards synaptic targets is vital for Mauthner survival. We also demonstrate that symmetric spiral fiber input to Mauthner cells is critical for escape direction, which is necessary to respond to directional threats. Moreover, we identify distinct roles for Celsr3 and Celsr2, as Celsr3 is required for startle circuit development while Celsr2 is dispensable, though Celsr2 can partially compensate for loss of Celsr3 in Mauthner cells. This contrasts with facial branchiomotor neuron migration in the hindbrain, which requires Celsr2 while we find that Celsr3 is dispensable. Combined, our data uncover critical and distinct roles for individual PCP components during assembly of the acoustic startle hindbrain circuit.

This study focuses on the design, production and testing of a micropatterned PDMS surface, featuring micropillars and microchannels to study the regeneration of individual axons of PC12 nerve cells after injury. Micropillar organization on the surface was designed to restrict the PC12 cell bodies while axons were guided into microchannels, allowing observation of individual axons. Surfaces were coated with poly(L-lysine) to improve cell attachment and proliferation. Netrin-1, a chemoattractant molecule and axonal elongation enhancer, was introduced in a gelatin methacrylate (GelMA) hydrogel carrier at the opposite end of the channels. Schwann cells (SC) were co-cultured with PC12 cells to enhance axon extension. MTT and Live-Dead assays showed 90% viability of the PC12 and Schwann cells on surfaces. The average PC12 axon length in the channels was 51 ± 19 μm; which increased to 75 ± 16 μm and 177 ± 31 μm upon co-culture with Schwann cells and Netrin-1 incorporation along with co-culturing, respectively, showing their synergistic effect on axon elongation. To study axon damage and regeneration processes, PC12 axons extended into the microchannels were cut using a microtome blade. An increase in the expression of injury markers ATF3, GFAP and S100β was observed after the injury with confocal microscopy, and their decrease from days 14 to 21 indicated the initiation of axon regeneration. The platform consisting of patterned PDMS surface, Schwann cells and Netrin-1 holds potential as a valuable tool for nerve damage and repair studies, and for in vitro testing of novel nerve tissue engineering strategies. Highlights A novel micropatterned platform was designed for neural axon guidance and regeneration studies. Axons of PC12 neural cells were directed into microchannels. Presence of Schwann cells and chemoattractant Netrin-1 enhanced axon extension. Regeneration of severed axons were detected by the expression intensity of the injury markers ATF3, GFAP and S100β.

Brain self-assembly is thought to be initiated by pioneer neurons whose identity is unknown. Rapti et al ., addressing this long-standing mystery, uncover key steps in forming the brain-like nerve ring of C. elegans . Glia initiate the structure, using Netrin to guide pioneer neurons, whose identity is characterized. Glia and pioneer neurons then together direct follower-axon guidance using redundant guidance factors. Brain assembly is hypothesized to begin when pioneer axons extend over non-neuronal cells, forming tracts guiding follower axons. Yet pioneer-neuron identities, their guidance substrates, and their interactions are not well understood. Here, using time-lapse embryonic imaging, genetics, protein-interaction, and functional studies, we uncover the early events of C. elegans brain assembly. We demonstrate that C. elegans glia are key for assembly initiation, guiding pioneer and follower axons using distinct signals. Pioneer sublateral neurons, with unique growth properties, anatomy, and innervation, cooperate with glia to mediate follower-axon guidance. We further identify a Chimaerin (CHIN-1)– Furin (KPC-1) double-mutant that severely disrupts assembly. CHIN-1 and KPC-1 function noncanonically, in glia and pioneer neurons, for guidance-cue trafficking. We exploit this bottleneck to define roles for glial Netrin and Semaphorin in pioneer- and follower-axon guidance, respectively, and for glial and pioneer-neuron Flamingo (CELSR) in follower-axon navigation. Taken together, our studies reveal previously undescribed glial roles in pioneer-axon guidance, suggesting conserved principles of brain assembly.

In the developing nervous system, axons navigate through complex terrains that change depending on when and where outgrowth begins. For instance, in the developing cochlea, spiral ganglion neurons extend their peripheral processes through a growing and heterogeneous environment en route to their final targets, the hair cells. Although the basic principles of axon guidance are well established, it remains unclear how axons adjust strategies over time and space. Here, we show that neurons with different positions in the spiral ganglion employ different guidance mechanisms, with evidence for both glia-guided growth and fasciculation along a neuronal scaffold. Processes from neurons in the rear of the ganglion are more directed and grow faster than those from neurons at the border of the ganglion. Further, processes at the wavefront grow more efficiently when in contact with glial precursors growing ahead of them. These findings suggest a tiered mechanism for reliable axon guidance. In developing embryos, axons grow through complex and dynamic terrains. Here, the authors show that spiral ganglion neurons in the developing mouse cochlea extend leading axons that interact with a scaffold of glial precursors, with follower axons fasciculating on top.

Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized by progressive memory decline and cognitive dysfunctions. Although the causes of AD have not yet been established, many mechanisms have been proposed. Axon-guidance molecules play the roles in the occurrence and development of AD by participating in different mechanisms. Therefore, what roles do axon-guidance molecules play in AD? This study aimed at elucidating how axon-guidance molecules Netrins, Slits, Semaphorins, and Ephrins regulate the levels of Aβ, hyperphosphorylation of tau protein, Reelin, and other ways through different signaling pathways, in order to show the roles of axon-guidance molecules in the occurrence and development of AD. And it is hoped that this study can provide a theoretical basis and new perspectives in the search for new therapeutic targets for AD.

Axon guidance requires interactions between extracellular signaling molecules and transmembrane receptors, but how appropriate context-dependent decisions are coordinated outside the cell remains unclear. Here we show that the transmembrane glycoprotein Dystroglycan interacts with a changing set of environmental cues that regulate the trajectories of extending axons throughout the mammalian brain and spinal cord. Dystroglycan operates primarily as an extracellular scaffold during axon guidance, as it functions non-cell autonomously and does not require signaling through its intracellular domain. We identify the transmembrane receptor Celsr3/Adgrc3 as a binding partner for Dystroglycan, and show that this interaction is critical for specific axon guidance events in vivo. These findings establish Dystroglycan as a multifunctional scaffold that coordinates extracellular matrix proteins, secreted cues, and transmembrane receptors to regulate axon guidance.

Axon pathfinding is critical for nervous system development, and it is orchestrated by molecular cues that activate receptors on the axonal growth cone. Robo family receptors bind Slit guidance cues to mediate axon repulsion. In mammals, the divergent family member Robo3 does not bind Slits, but instead signals axon repulsion from its own ligand, NELL2. Conversely, canonical Robos do not mediate NELL2 signaling. Here, we present the structures of NELL-Robo3 complexes, identifying a mode of ligand engagement for Robos that is orthogonal to Slit binding. We elucidate the structural basis for differential binding between NELL and Robo family members and show that NELL2 repulsive activity is a function of its Robo3 affinity and is enhanced by ligand trimerization. Our results reveal a mechanism of oligomerization-induced Robo activation for axon guidance and shed light on Robo family member ligand binding specificity, conformational variability, divergent modes of signaling, and evolution. Robo3 is a divergent, multifunctional member of the Robo receptor family that mediates axon guidance by its ligand NELL2 instead of the canonical Slit ligands. Here, the authors present the crystal structures of human Robo3 in complex with NELL1 and NELL2, and they show through biophysical and functional assays how NELL-Robo3 affinity and ligand-induced receptor multimerization control axon guidance activity.