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Frontiers in Cellular Neuroscience 2015The guidance of axons to their proper targets is not only a crucial event in neurodevelopment, but also a potential therapeutic target for neural repair. Axon guidance... (Review)
Review
The guidance of axons to their proper targets is not only a crucial event in neurodevelopment, but also a potential therapeutic target for neural repair. Axon guidance is mediated by various chemo- and haptotactic cues, as well as the mechanical interactions between the cytoskeleton and the extracellular matrix (ECM). Axonal growth cones, dynamic ends of growing axons, convert external stimuli to biochemical signals, which, in turn, are translated into behavior, e.g., turning or retraction, via cytoskeleton-matrix linkages. Despite the inherent mechanical nature of the problem, the role of mechanics in axon guidance is poorly understood. Recent years has witnessed the application of a range of microtechnologies in neurobiology, from microfluidic circuits to single molecule force spectroscopy. In this mini-review, we describe microtechnologies geared towards dissecting the mechanical aspects of axon guidance, divided into three categories: controlling the growth cone microenvironment, stimulating growth cones with externally applied forces, and measuring forces exerted by the growth cones. A particular emphasis is given to those studies that combine multiple techniques, as dictated by the complexity of the problem.
PubMed: 26283918
DOI: 10.3389/fncel.2015.00282 -
Frontiers in Endocrinology 2022The islets of Langerhans, responsible for regulating blood glucose in vertebrates, are clusters of endocrine cells distributed throughout the exocrine pancreas. The... (Review)
Review
The islets of Langerhans, responsible for regulating blood glucose in vertebrates, are clusters of endocrine cells distributed throughout the exocrine pancreas. The spatial architecture of the different cell types within the islets controls cell-cell communication and impacts their ability to collectively regulate glucose. Islets rely on a range of chemotactic and adhesive cues to establish and manage intercellular relationships. Growing evidence indicates that axon guidance molecules such as Slit-Robo, Semaphorin-Neuropilin, Ephrin-Eph, and Netrins, influence endocrine progenitors' cell migration to establish correct architecture during islet morphogenesis, as well as directly regulating physical cell-cell communication in the mature islet to coordinate hormone secretion. In this mini-review, we discuss what is known and not yet known about how axon guidance molecules contribute to islet morphogenesis and function.
Topics: Animals; Axon Guidance; Cell Communication; Endocrine Cells; Islets of Langerhans
PubMed: 35498433
DOI: 10.3389/fendo.2022.869780 -
EMBO Molecular Medicine Mar 2023The genetic changes sustaining the development of cancers of unknown primary (CUP) remain elusive. The whole-exome genomic profiling of 14 rigorously selected CUP...
The genetic changes sustaining the development of cancers of unknown primary (CUP) remain elusive. The whole-exome genomic profiling of 14 rigorously selected CUP samples did not reveal specific recurring mutation in known driver genes. However, by comparing the mutational landscape of CUPs with that of most other human tumor types, it emerged a consistent enrichment of changes in genes belonging to the axon guidance KEGG pathway. In particular, G842C mutation of PlexinB2 (PlxnB2) was predicted to be activating. Indeed, knocking down the mutated, but not the wild-type, PlxnB2 in CUP stem cells resulted in the impairment of self-renewal and proliferation in culture, as well as tumorigenic capacity in mice. Conversely, the genetic transfer of G842C-PlxnB2 was sufficient to promote CUP stem cell proliferation and tumorigenesis in mice. Notably, G842C-PlxnB2 expression in CUP cells was associated with basal EGFR phosphorylation, and EGFR blockade impaired the viability of CUP cells reliant on the mutated receptor. Moreover, the mutated PlxnB2 elicited CUP cell invasiveness, blocked by EGFR inhibitor treatment. In sum, we found that a novel activating mutation of the axon guidance gene PLXNB2 sustains proliferative autonomy and confers invasive properties to stem cells isolated from cancers of unknown primary, in EGFR-dependent manner.
Topics: Animals; Humans; Mice; Axon Guidance; ErbB Receptors; Mutation; Neoplasm Recurrence, Local; Neoplasms, Unknown Primary; Nerve Tissue Proteins; Neoplastic Stem Cells
PubMed: 36722641
DOI: 10.15252/emmm.202216104 -
Current Topics in Developmental Biology 2021As the nervous system develops, newly differentiated neurons need to extend their axons toward their synaptic targets to form functional neural circuits. During this... (Review)
Review
As the nervous system develops, newly differentiated neurons need to extend their axons toward their synaptic targets to form functional neural circuits. During this highly dynamic process of axon pathfinding, guidance receptors expressed at the tips of motile axons interact with soluble guidance cues or membrane tethered molecules present in the environment to be either attracted toward or repelled away from the source of these cues. As competing cues are often present at the same location and during the same developmental period, guidance receptors need to be both spatially and temporally regulated in order for the navigating axons to make appropriate guidance decisions. This regulation is exerted by a diverse array of molecular mechanisms that have come into focus over the past several decades and these mechanisms ensure that the correct complement of surface receptors is present on the growth cone, a fan-shaped expansion at the tip of the axon. This dynamic, highly motile structure is defined by a lamellipodial network lining the periphery of the growth cone interspersed with finger-like filopodial projections that serve to explore the surrounding environment. Once axon guidance receptors are deployed at the right place and time at the growth cone surface, they respond to their respective ligands by initiating a complex set of signaling events that serve to rearrange the growth cone membrane and the actin and microtubule cytoskeleton to affect axon growth and guidance. In this review, we highlight recent advances that shed light on the rich complexity of mechanisms that regulate axon guidance receptor distribution, activation and downstream signaling.
Topics: Axon Guidance
PubMed: 33706917
DOI: 10.1016/bs.ctdb.2020.11.008 -
Journal of Developmental Biology Feb 2017As reflected by the term morphogen, molecules such as Shh and Wnts were identified based on their role in early development when they instruct precursor cells to adopt a... (Review)
Review
As reflected by the term morphogen, molecules such as Shh and Wnts were identified based on their role in early development when they instruct precursor cells to adopt a specific cell fate. Only much later were they implicated in neural circuit formation. Both in vitro and in vivo studies indicated that morphogens direct axons during their navigation through the developing nervous system. Today, the best understood role of Shh and Wnt in axon guidance is their effect on commissural axons in the spinal cord. Shh was shown to affect commissural axons both directly and indirectly via its effect on Wnt signaling. In fact, throughout neural circuit formation there is cross-talk and collaboration of Shh and Wnt signaling. Thus, although the focus of this review is on the role of Shh in neural circuit formation, a separation from Wnt signaling is not possible.
PubMed: 29615560
DOI: 10.3390/jdb5010002 -
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 -
Cell Adhesion & Migration 2013The peripheral axons of vertebrate tactile somatosensory neurons travel long distances from ganglia just outside the central nervous system to the skin. Once in the skin... (Review)
Review
The peripheral axons of vertebrate tactile somatosensory neurons travel long distances from ganglia just outside the central nervous system to the skin. Once in the skin these axons form elaborate terminals whose organization must be regionally patterned to detect and accurately localize different kinds of touch stimuli. This review describes key studies that identified choice points for somatosensory axon growth cones and the extrinsic molecular cues that function at each of those steps. While much has been learned in the past 20 years about the guidance of these axons, there is still much to be learned about how the peripheral axons of different kinds of somatosensory neurons adopt different trajectories and form specific terminal structures.
Topics: Animals; Axons; Gene Expression Regulation, Developmental; Morphogenesis; Skin
PubMed: 23670092
DOI: 10.4161/cam.25000 -
Basic Research in Cardiology Jan 2021Cardiovascular pathologies are often induced by inflammation. The associated changes in the inflammatory response influence vascular endothelial biology; they complicate... (Review)
Review
Cardiovascular pathologies are often induced by inflammation. The associated changes in the inflammatory response influence vascular endothelial biology; they complicate the extent of ischaemia and reperfusion injury, direct the migration of immune competent cells and activate platelets. The initiation and progression of inflammation is regulated by the classical paradigm through the system of cytokines and chemokines. Therapeutic approaches have previously used this knowledge to control the extent of cardiovascular changes with varying degrees of success. Neuronal guidance proteins (NGPs) have emerged in recent years and have been shown to be significantly involved in the control of tissue inflammation and the mechanisms of immune cell activation. Therefore, proteins of this class might be used in the future as targets to control the extent of inflammation in the cardiovascular system. In this review, we describe the role of NGPs during cardiovascular inflammation and highlight potential therapeutic options that could be explored in the future.
Topics: Animals; Atherosclerosis; Axon Guidance; Humans; Inflammation; Inflammation Mediators; Intercellular Signaling Peptides and Proteins; Myocardial Reperfusion Injury; Myocardium; Nerve Tissue Proteins; Plaque, Atherosclerotic; Signal Transduction; Thrombosis
PubMed: 33511463
DOI: 10.1007/s00395-021-00847-x -
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 -
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