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Brain : a Journal of Neurology Apr 2022Understanding new modulators of axon regeneration is central to neural repair. Our previous work demonstrated critical roles of atypical cadherin Celsr2 during neural...
Understanding new modulators of axon regeneration is central to neural repair. Our previous work demonstrated critical roles of atypical cadherin Celsr2 during neural development, including cilia organization, neuron migration and axon navigation. Here, we address its role in axon regeneration. We show that Celsr2 is highly expressed in both mouse and human spinal motor neurons. Celsr2 knockout promotes axon regeneration and fasciculation in mouse cultured spinal explants. Similarly, cultured Celsr2 mutant motor neurons extend longer neurites and larger growth cones, with increased expression of end-binding protein 3 and higher potassium-induced calcium influx. Mice with Celsr2 conditional knockout in spinal motor neurons do not exhibit any behavioural deficits; however, after branchial plexus injury, axon regeneration and functional forelimb locomotor recovery are significantly improved. Similarly, knockdown of CELSR2 using shRNA interference in cultured human spinal motor explants and motor neurons increases axonal fasciculation and growth. In mouse adult spinal cord after root avulsion, in mouse embryonic spinal cords, and in cultured human motor neurons, Celsr2 downregulation is accompanied by increased levels of GTP-bound Rac1 and Cdc42, and of JNK and c-Jun. In conclusion, Celsr2 negatively regulates motor axon regeneration and is a potential target to improve neural repair.
Topics: Animals; Axon Fasciculation; Axons; Cadherins; Humans; Mice; Motor Neurons; Nerve Regeneration; Spinal Cord; Spinal Cord Injuries
PubMed: 34983065
DOI: 10.1093/brain/awab317 -
International Journal of Molecular... Jul 2020The development of neural circuits is a complex process that relies on the proper navigation of axons through their environment to their appropriate targets. While... (Review)
Review
The development of neural circuits is a complex process that relies on the proper navigation of axons through their environment to their appropriate targets. While axon-environment and axon-target interactions have long been known as essential for circuit formation, communication between axons themselves has only more recently emerged as another crucial mechanism. Trans-axonal signaling governs many axonal behaviors, including fasciculation for proper guidance to targets, defasciculation for pathfinding at important choice points, repulsion along and within tracts for pre-target sorting and target selection, repulsion at the target for precise synaptic connectivity, and potentially selective degeneration for circuit refinement. This review outlines the recent advances in identifying the molecular mechanisms of trans-axonal signaling and discusses the role of axon-axon interactions during the different steps of neural circuit formation.
Topics: Animals; Axons; Fasciculation; Growth Cones; Neural Conduction; Signal Transduction
PubMed: 32708320
DOI: 10.3390/ijms21145170 -
Genetics Nov 2016The correct wiring of neuronal circuits depends on outgrowth and guidance of neuronal processes during development. In the past two decades, great progress has been made... (Review)
Review
The correct wiring of neuronal circuits depends on outgrowth and guidance of neuronal processes during development. In the past two decades, great progress has been made in understanding the molecular basis of axon outgrowth and guidance. Genetic analysis in Caenorhabditis elegans has played a key role in elucidating conserved pathways regulating axon guidance, including Netrin signaling, the slit Slit/Robo pathway, Wnt signaling, and others. Axon guidance factors were first identified by screens for mutations affecting animal behavior, and by direct visual screens for axon guidance defects. Genetic analysis of these pathways has revealed the complex and combinatorial nature of guidance cues, and has delineated how cues guide growth cones via receptor activity and cytoskeletal rearrangement. Several axon guidance pathways also affect directed migrations of non-neuronal cells in C. elegans, with implications for normal and pathological cell migrations in situations such as tumor metastasis. The small number of neurons and highly stereotyped axonal architecture of the C. elegans nervous system allow analysis of axon guidance at the level of single identified axons, and permit in vivo tests of prevailing models of axon guidance. C. elegans axons also have a robust capacity to undergo regenerative regrowth after precise laser injury (axotomy). Although such axon regrowth shares some similarities with developmental axon outgrowth, screens for regrowth mutants have revealed regeneration-specific pathways and factors that were not identified in developmental screens. Several areas remain poorly understood, including how major axon tracts are formed in the embryo, and the function of axon regeneration in the natural environment.
Topics: Actin Cytoskeleton; Animals; Axon Guidance; Caenorhabditis elegans; Nerve Regeneration
PubMed: 28114100
DOI: 10.1534/genetics.115.186262 -
Seminars in Cell & Developmental Biology Sep 2017The δ-protocadherins comprise a small family of homophilic cell adhesion molecules within the larger cadherin superfamily. They are essential for neural development as... (Review)
Review
The δ-protocadherins comprise a small family of homophilic cell adhesion molecules within the larger cadherin superfamily. They are essential for neural development as mutations in these molecules give rise to human neurodevelopmental disorders, such as schizophrenia and epilepsy, and result in behavioral defects in animal models. Despite their importance to neural development, a detailed understanding of their mechanisms and the ways in which their loss leads to changes in neural function is lacking. However, recent results have begun to reveal roles for the δ-protocadherins in both regulation of neurogenesis and lineage-dependent circuit assembly, as well as in contact-dependent motility and selective axon fasciculation. These evolutionarily conserved mechanisms could have a profound impact on the robust assembly of the vertebrate nervous system. Future work should be focused on unraveling the molecular mechanisms of the δ-protocadherins and understanding how this family functions broadly to regulate neural development.
Topics: Animals; Cadherins; Humans; Models, Biological; Nerve Net; Nervous System Diseases; Phylogeny; Synapses
PubMed: 28751249
DOI: 10.1016/j.semcdb.2017.07.037 -
Molecules and Cells Aug 2021Decoding the molecular mechanisms underlying axon guidance is key to precise understanding of how complex neural circuits form during neural development. Although... (Review)
Review
Decoding the molecular mechanisms underlying axon guidance is key to precise understanding of how complex neural circuits form during neural development. Although substantial progress has been made over the last three decades in identifying numerous axon guidance molecules and their functional roles, little is known about how these guidance molecules collaborate to steer growth cones to their correct targets. Recent studies in point to the importance of the combinatorial action of guidance molecules, and further show that selective fasciculation and defasciculation at specific choice points serve as a fundamental strategy for motor axon guidance. Here, I discuss how attractive and repulsive guidance cues cooperate to ensure the recognition of specific choice points that are inextricably linked to selective fasciculation and defasciculation, and correct pathfinding decision-making.
Topics: Animals; Axon Fasciculation; Axon Guidance; Drosophila melanogaster; Motor Neurons; Muscles; Neuromuscular Junction
PubMed: 34385406
DOI: 10.14348/molcells.2021.0129 -
Frontiers in Cellular Neuroscience 2014Brain wiring is a highly intricate process in which trillions of neuronal connections are established. Its initial phase is particularly crucial in establishing the... (Review)
Review
Brain wiring is a highly intricate process in which trillions of neuronal connections are established. Its initial phase is particularly crucial in establishing the general framework of neuronal circuits. During this early step, differentiating neurons extend axons, which reach their target by navigating through a complex environment with extreme precision. Research in the past 20 years has unraveled a vast and complex array of chemotropic cues that guide the leading tip of axons, the growth cone, throughout its journey. Tight regulation of these cues, and of their receptors and signaling pathways, is necessary for the high degree of accuracy required during circuit formation. However, little is known about the nature of regulatory molecules or mechanisms fine-tuning axonal cue response. Here we review recent, and somewhat fragmented, research on the possibility that microRNAs (miRNAs) could be key fine-tuning regulatory molecules in axon guidance. miRNAs appear to shape long-range axon guidance, fasciculation and targeting. We also present several lines of evidence suggesting that miRNAs could have a compartmentalized and differential action at the cell soma, and within axons and growth cones.
PubMed: 24672429
DOI: 10.3389/fncel.2014.00078 -
Cell Reports Jan 2020Neuronal migration, axon fasciculation, and axon guidance need to be closely coordinated for neural circuit assembly. Spinal motor neurons (MNs) face unique challenges...
Neuronal migration, axon fasciculation, and axon guidance need to be closely coordinated for neural circuit assembly. Spinal motor neurons (MNs) face unique challenges during development because their cell bodies reside within the central nervous system (CNS) and their axons project to various targets in the body periphery. The molecular mechanisms that contain MN somata within the spinal cord while allowing their axons to exit the CNS and navigate to their final destinations remain incompletely understood. We find that the MN cell surface protein TAG-1 anchors MN cell bodies in the spinal cord to prevent their emigration, mediates motor axon fasciculation during CNS exit, and guides motor axons past dorsal root ganglia. TAG-1 executes these varied functions in MN development independently of one another. Our results identify TAG-1 as a key multifunctional regulator of MN wiring that coordinates neuronal migration, axon fasciculation, and axon guidance.
Topics: Animals; Axon Guidance; Axons; COS Cells; Cell Line; Cell Movement; Chlorocebus aethiops; Contactin 2; Fasciculation; Ganglia, Spinal; Gene Expression Regulation, Developmental; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Neurons; Neurogenesis; Signal Transduction; Spinal Cord
PubMed: 31995756
DOI: 10.1016/j.celrep.2019.12.085 -
Proceedings of the National Academy of... Feb 2017Although many aspects of optic pathway development are beginning to be understood, the mechanisms promoting the growth of retinal ganglion cell (RGC) axons toward visual...
Although many aspects of optic pathway development are beginning to be understood, the mechanisms promoting the growth of retinal ganglion cell (RGC) axons toward visual targets remain largely unknown. Down syndrome cell adhesion molecule () is expressed by mouse RGCs shortly after they differentiate at embryonic day 12 and is essential for multiple aspects of postnatal visual system development. Here we show that is also required during embryonic development for the fasciculation and growth of RGC axons. is expressed along the developing optic pathway in a pattern consistent with a role in regulating RGC axon outgrowth. In mice carrying spontaneous mutations in ( ; , RGC axons pathfind normally, but growth from the chiasm toward their targets is impaired, resulting in a delay in RGC axons reaching the dorsal thalamus compared with that seen in wild-type littermates. Conversely, gain of function results in exuberant growth into the dorsal thalamus. The growth of ipsilaterally projecting axons is particularly affected. Axon organization in the optic chiasm and tract and RGC growth cone morphologies are also altered in mutants. In vitro DSCAM promotes RGC axon growth and fasciculation, and can act independently of cell contact. In vitro and in situ DSCAM is required both in the RGC axons and in their environment for the promotion of axon outgrowth, consistent with a homotypic mode of action. These findings identify DSCAM as a permissive signal that promotes the growth and fasciculation of RGC axons, controlling the timing of when RGC axons reach their targets.
Topics: Animals; Axon Fasciculation; Axons; COS Cells; Cell Adhesion Molecules; Chlorocebus aethiops; Gene Expression Regulation, Developmental; Growth Cones; HEK293 Cells; Humans; In Situ Hybridization; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mutation; Optic Chiasm; Retina; Retinal Ganglion Cells; Visual Pathways
PubMed: 28137836
DOI: 10.1073/pnas.1618606114 -
Scientific Reports Sep 2020Intra-retinal axon guidance involves a coordinated expression of transcription factors, axon guidance genes, and secretory molecules within the retina. Pax6, the master...
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 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.
Topics: Animals; Axon Fasciculation; Axon Guidance; Cell Differentiation; Extracellular Matrix; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurogenesis; PAX6 Transcription Factor; Pregnancy; RNA-Seq; Receptor, EphB1; Retina; Retinal Ganglion Cells; Semaphorins
PubMed: 32999322
DOI: 10.1038/s41598-020-72828-4 -
Neuron Mar 2018Axon guidance involves the spatiotemporal interplay between guidance cues and membrane-bound cell-surface receptors, present on the growth cone of the axon. Netrin-1 is...
Axon guidance involves the spatiotemporal interplay between guidance cues and membrane-bound cell-surface receptors, present on the growth cone of the axon. Netrin-1 is a prototypical guidance cue that binds to deleted in colorectal cancer (DCC), and it has been proposed that the guidance cue Draxin modulates this interaction. Here, we present structural snapshots of Draxin/DCC and Draxin/Netrin-1 complexes, revealing a triangular relationship that affects Netrin-mediated haptotaxis and fasciculation. Draxin interacts with DCC through the N-terminal four immunoglobulin domains, and Netrin-1 through the EGF-3 domain, in the same region where DCC binds. Netrin-1 and DCC bind to adjacent sites on Draxin, which appears to capture Netrin-1 and tether it to the DCC receptor. We propose the conformational flexibility of the single-pass membrane receptor DCC is used to promote fasciculation and regulate axon guidance through concerted Netrin-1/Draxin binding. VIDEO ABSTRACT.
Topics: Amino Acid Sequence; Animals; Axon Guidance; COS Cells; Chlorocebus aethiops; DCC Receptor; HEK293 Cells; Humans; Intercellular Signaling Peptides and Proteins; Nerve Tissue Proteins; Netrin-1; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary
PubMed: 29503192
DOI: 10.1016/j.neuron.2018.02.010