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Gastroenterology Sep 2019Little is known about mechanisms of perineural invasion (PNI) by pancreatic ductal adenocarcinomas (PDAs) or other tumors. Annexin A2 (ANXA2) regulates secretion of...
BACKGROUND & AIMS
Little is known about mechanisms of perineural invasion (PNI) by pancreatic ductal adenocarcinomas (PDAs) or other tumors. Annexin A2 (ANXA2) regulates secretion of SEMA3D, an axon guidance molecule, which binds and activates the receptor PLXND1 to promote PDA invasion and metastasis. We investigated whether axon guidance molecules promote PNI and metastasis by PDA cells in mice.
METHODS
We performed studies in a dorsal root ganglion (DRG) invasion system, wild-type C57BL/6 mice (controls), mice with peripheral sensory neuron-specific disruption of PlxnD1 (PLAC mice), LSL-KRAS;LSL-TP53;PDX-1-CRE (KPC) mice, and KPC mice crossed with ANXA2-knockout mice (KPCA mice). PDA cells were isolated from KPC mice and DRG cells were isolated from control mice. Levels of SEMA3D or ANXA2 were knocked down in PDA cells with small hairpin and interfering RNAs and cells were analyzed by immunoblots in migration assays, with DRGs and with or without antibodies against PLXND1. PDA cells were injected into the pancreas of control and PLAC mice, growth of tumors was assessed, and tumor samples were analyzed by histology. DRG cells were incubated with SEMA3D and analyzed by live imaging. We measured levels of SEMA3D and PLXND1 in PDA specimens from patients with PNI and calculated distances between tumor cells and nerves.
RESULTS
DRG cells increase the migration of PDC cells in invasion assays; knockdown of SEMA3D in PDA cells or antibody blockade of PLXND1 on DRG cells reduced this invasive activity. In mice, orthotopic tumors grown from PDA cells with knockdown of SEMA3D, and in PLAC mice, orthotopic tumors grown from PDA cells, had reduced innervation and formed fewer metastases than orthotopic tumors grown from PDA cells in control mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI.
CONCLUSIONS
DRG cells increase the migratory and invasive activities of pancreatic cancer cells, via secretion of SEMA3D by pancreatic cells and activation of PLXND1 on DRGs. Knockdown of SEMA3D and loss of neural PLXND1 reduces innervation of orthotopic PDAs and metastasis in mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. Strategies to disrupt the axon guidance pathway mediated by SEMA3D and PLXND1 might be developed to slow progression of PDA.
Topics: Animals; Annexin A2; Axon Guidance; Carcinoma, Pancreatic Ductal; Cell Communication; Cell Movement; Ganglia, Spinal; Gene Expression Regulation, Neoplastic; Genes, p53; Genes, ras; Genetic Predisposition to Disease; Homeodomain Proteins; Humans; Intracellular Signaling Peptides and Proteins; Membrane Glycoproteins; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Invasiveness; Nerve Tissue Proteins; Neuronal Outgrowth; Pancreatic Neoplasms; Phenotype; Semaphorins; Signal Transduction; Trans-Activators; Tumor Cells, Cultured
PubMed: 31163177
DOI: 10.1053/j.gastro.2019.05.065 -
Molecules and Cells Feb 2022Neurons-on-a-Chip technology has been developed to provide diverse neuro-tools to study neuritogenesis, synaptogensis, axon guidance, and network dynamics. The two core... (Review)
Review
Neurons-on-a-Chip technology has been developed to provide diverse neuro-tools to study neuritogenesis, synaptogensis, axon guidance, and network dynamics. The two core enabling technologies are soft-lithography and microelectrode array technology. Soft lithography technology made it possible to fabricate microstamps and microfluidic channel devices with a simple replica molding method in a biological laboratory and innovatively reduced the turn-around time from assay design to chip fabrication, facilitating various experimental designs. To control nerve cell behaviors at the single cell level via chemical cues, surface biofunctionalization methods and micropatterning techniques were developed. Microelectrode chip technology, which provides a functional readout by measuring the electrophysiological signals from individual neurons, has become a popular platform to investigate neural information processing in networks. Due to these key advances, it is possible to study the relationship between the network structure and functions, and they have opened a new era of neurobiology and will become standard tools in the near future.
Topics: Lab-On-A-Chip Devices; Neurons; Oligonucleotide Array Sequence Analysis
PubMed: 35236782
DOI: 10.14348/molcells.2022.2023 -
The Journal of Neuroscience : the... Oct 2016Although much is known about the regenerative capacity of retinal ganglion cells, very significant barriers remain in our ability to restore visual function following... (Review)
Review
Although much is known about the regenerative capacity of retinal ganglion cells, very significant barriers remain in our ability to restore visual function following traumatic injury or disease-induced degeneration. Here we summarize our current understanding of the factors regulating axon guidance and target engagement in regenerating axons, and review the state of the field of neural regeneration, focusing on the visual system and highlighting studies using other model systems that can inform analysis of visual system regeneration. This overview is motivated by a Society for Neuroscience Satellite meeting, "Reconnecting Neurons in the Visual System," held in October 2015 sponsored by the National Eye Institute as part of their "Audacious Goals Initiative" and co-organized by Carol Mason (Columbia University) and Michael Crair (Yale University). The collective wisdom of the conference participants pointed to important gaps in our knowledge and barriers to progress in promoting the restoration of visual system function. This article is thus a summary of our existing understanding of visual system regeneration and provides a blueprint for future progress in the field.
Topics: Animals; Axons; Brain; Humans; Ocular Physiological Phenomena; Optic Nerve; Retinal Ganglion Cells; Visual Pathways
PubMed: 27798125
DOI: 10.1523/JNEUROSCI.1711-16.2016 -
Experimental Neurobiology Jun 2019Axon guidance molecules (AGMs), such as Netrins, Semaphorins, and Ephrins, have long been known to regulate axonal growth in the developing nervous system.... (Review)
Review
Axon guidance molecules (AGMs), such as Netrins, Semaphorins, and Ephrins, have long been known to regulate axonal growth in the developing nervous system. Interestingly, the chemotactic properties of AGMs are also important in the postnatal period, such as in the regulation of immune and inflammatory responses. In particular, AGMs play pivotal roles in inflammation of the nervous system, by either stimulating or inhibiting inflammatory responses, depending on specific ligand-receptor combinations. Understanding such regulatory functions of AGMs in neuroinflammation may allow finding new molecular targets to treat neurodegenerative diseases, in which neuroinflammation underlies aetiology and progression.
PubMed: 31308791
DOI: 10.5607/en.2019.28.3.311 -
Biomolecules Jan 2021Axonal trajectories and neural circuit activities strongly rely on a complex system of molecular cues that finely orchestrate the patterning of neural commissures.... (Review)
Review
Axonal trajectories and neural circuit activities strongly rely on a complex system of molecular cues that finely orchestrate the patterning of neural commissures. Several of these axon guidance molecules undergo continuous recycling during brain development, according to incompletely understood intracellular mechanisms, that in part rely on endocytic and autophagic cascades. Based on their pivotal role in both pathways, lysosomes are emerging as a key hub in the sophisticated regulation of axonal guidance cue delivery, localization, and function. In this review, we will attempt to collect some of the most relevant research on the tight connection between lysosomal function and axon guidance regulation, providing some proof of concepts that may be helpful to understanding the relation between lysosomal storage disorders and neurodegenerative diseases.
Topics: Autophagy; Axon Guidance; Axons; Brain; Endosomes; Ephrins; Humans; Lysosomal Storage Diseases; Lysosomes; Netrins; Neurodegenerative Diseases; Neurons; Semaphorins
PubMed: 33573025
DOI: 10.3390/biom11020191 -
Cells Oct 2022Chronic pain is a debilitating condition that influences the social, economic, and psychological aspects of patients' lives. Hence, the need for better treatment is... (Review)
Review
Chronic pain is a debilitating condition that influences the social, economic, and psychological aspects of patients' lives. Hence, the need for better treatment is drawing extensive interest from the research community. Developmental molecules such as Wnt, ephrins, and semaphorins are acknowledged as central players in the proper growth of a biological system. Their receptors and ligands are expressed in a wide variety in both neurons and glial cells, which are implicated in pain development, maintenance, and resolution. Thereby, it is not surprising that the impairment of those pathways affects the activities and functions of the entire cell. Evidence indicates aberrant activation of their pathways in the nervous system in rodent models of chronic pain. In those conditions, Wnt, ephrin, and semaphorin signaling participate in enhancing neuronal excitability, peripheral sensitization, synaptic plasticity, and the production and release of inflammatory cytokines. This review summarizes the current knowledge on three main developmental pathways and their mechanisms linked with the pathogenesis and progression of pain, considering their impacts on neuronal and glial cells in experimental animal models. Elucidations of the downstream pathways may provide a new mechanism for the involvement of Wnt, ephrin, and semaphorin pathways in pain chronicity.
Topics: Animals; Axon Guidance; Chronic Pain; Cytokines; Ephrins; Semaphorins
PubMed: 36231105
DOI: 10.3390/cells11193143 -
Neural Regeneration Research Jul 2017Receptor for activated C kinase 1 (RACK1) is an evolutionarily conserved scaffolding protein within the tryptophan-aspartate (WD) repeat family of proteins. RACK1 can... (Review)
Review
Receptor for activated C kinase 1 (RACK1) is an evolutionarily conserved scaffolding protein within the tryptophan-aspartate (WD) repeat family of proteins. RACK1 can bind multiple signaling molecules concurrently, as well as stabilize and anchor proteins. RACK1 also plays an important role at focal adhesions, where it acts to regulate cell migration. In addition, RACK1 is a ribosomal binding protein and thus, regulates translation. Despite these numerous functions, little is known about how RACK1 regulates nervous system development. Here, we review three studies that examine the role of RACK1 in neural development. In brief, these papers demonstrate that (1) RACK-1, the homolog of mammalian RACK1, is required for axon guidance; (2) RACK1 is required for neurite extension of neuronally differentiated rat PC12 cells; and (3) RACK1 is required for axon outgrowth of primary mouse cortical neurons. Thus, it is evident that RACK1 is critical for appropriate neural development in a wide range of species, and future discoveries could reveal whether RACK1 and its signaling partners are potential targets for treatment of neurodevelopmental disorders or a therapeutic approach for axonal regeneration.
PubMed: 28852378
DOI: 10.4103/1673-5374.211175 -
F1000Research 2017During neural circuit formation, axons need to navigate to their target cells in a complex, constantly changing environment. Although we most likely have identified most... (Review)
Review
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.
PubMed: 28163913
DOI: 10.12688/f1000research.10126.1 -
International Journal of Molecular... Aug 2021During neuronal development and regeneration axons extend a cytoskeletal-rich structure known as the growth cone, which detects and integrates signals to reach its final... (Review)
Review
During neuronal development and regeneration axons extend a cytoskeletal-rich structure known as the growth cone, which detects and integrates signals to reach its final destination. The guidance cues "signals" bind their receptors, activating signaling cascades that result in the regulation of the growth cone cytoskeleton, defining growth cone advance, pausing, turning, or collapse. Even though much is known about guidance cues and their isolated mechanisms during nervous system development, there is still a gap in the understanding of the crosstalk between them, and about what happens after nervous system injuries. After neuronal injuries in mammals, only axons in the peripheral nervous system are able to regenerate, while the ones from the central nervous system fail to do so. Therefore, untangling the guidance cues mechanisms, as well as their behavior and characterization after axotomy and regeneration, are of special interest for understanding and treating neuronal injuries. In this review, we present findings on growth cone guidance and canonical guidance cues mechanisms, followed by a description and comparison of growth cone pathfinding mechanisms after axotomy, in regenerative and non-regenerative animal models.
Topics: Animals; Axon Guidance; Axons; Axotomy; Growth Cones; Humans; Nerve Regeneration; Signal Transduction
PubMed: 34361110
DOI: 10.3390/ijms22158344 -
Developmental Dynamics : An Official... Apr 2018Axons need to be properly guided to their targets to form synaptic connections, and this requires interactions between highly conserved extracellular and transmembrane... (Review)
Review
Axons need to be properly guided to their targets to form synaptic connections, and this requires interactions between highly conserved extracellular and transmembrane ligands and their cell surface receptors. The majority of studies on axon guidance signaling pathways have focused on the role of these pathways in rearranging the local cytoskeleton and plasma membrane in growth cones and axons. However, a smaller body of work has demonstrated that axon guidance signaling pathways also control gene expression via local translation and transcription. Recent studies on axon guidance ligands and receptors have begun to uncover the requirements for these alternative mechanisms in processes required for neural circuit formation: axon guidance, synaptogenesis, and cell migration. Understanding the mechanisms by which axon guidance signaling regulates local translation and transcription will create a more complete picture of neural circuit formation, and they may be applied more broadly to other tissues where axon guidance ligands and receptors are required for morphogenesis. Developmental Dynamics 247:571-580, 2018. © 2017 Wiley Periodicals, Inc.
Topics: Animals; Axon Guidance; Gene Expression Regulation; Humans; Ligands; Receptors, Cell Surface; Signal Transduction
PubMed: 29226467
DOI: 10.1002/dvdy.24609