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Handbook of Clinical Neurology 2020Development of the central nervous system (CNS) is a complex, dynamic process that involves a precisely orchestrated sequence of genetic, environmental, biochemical, and... (Review)
Review
Development of the central nervous system (CNS) is a complex, dynamic process that involves a precisely orchestrated sequence of genetic, environmental, biochemical, and physical factors from early embryonic stages to postnatal life. Duringthe past decade, great strides have been made to unravel mechanisms underlying human CNS development through the employment of modern genetic techniques and experimental approaches. In this chapter, we review the current knowledge regarding the main developmental processes and signaling mechanisms of (i) neurogenesis, (ii) neuronal migration, and (iii) axon guidance. We discuss mechanisms related to neural stem cells proliferation, migration, terminal translocation of neuronal progenitors, and axon guidance and pathfinding. For each section, we also provide a comprehensive overview of the underlying regulatory processes, including transcriptional, posttranscriptional, and epigenetic factors, and a myriad of signaling pathways that are pivotal to determine the fate of neuronal progenitors and newly formed migrating neurons. We further highlight how impairment of this complex regulating system, such as mutations in its core components, may cause cortical malformation, epilepsy, intellectual disability, and autism in humans. A thorough understanding of normal human CNS development is thus crucial to decipher mechanisms responsible for neurodevelopmental disorders and in turn guide the development of effective and targeted therapeutic strategies.
Topics: Axon Guidance; Cell Movement; Humans; Neurogenesis; Neurons; Signal Transduction
PubMed: 32958178
DOI: 10.1016/B978-0-444-64150-2.00004-6 -
Cytokine & Growth Factor Reviews Apr 2022Netrin-1 is a member of the laminin-like protein family and was initially identified as a potent chemotactic molecule involved in axonal guidance and cell migration... (Review)
Review
Netrin-1 is a member of the laminin-like protein family and was initially identified as a potent chemotactic molecule involved in axonal guidance and cell migration during embryonic development. Many studies have focused on the non-neural effects of netrin-1, and the results revealed that netrin-1 may be extensively involved in the regulation of angiogenesis, inflammation, tissue remodeling, and cancer. The pathogenic or protective effect of netrin-1 suggests that it may be a potential therapeutic target in multiple diseases. Netrin-1 plays different roles by interacting with its receptors, such as deleted in colorectal cancer (DCC)/neogenin and the uncoordinated-5 homolog family members (UNC5). Interestingly, contradictory actions in certain physiological pathways serve to highlight its manifold and often opposite effects on numerous physiological and pathophysiological processes. Netrin-1 regulates inflammation and leukocyte infiltration, suggesting roles for netrin-1 in the immune response. In this study, we review recent advances in the understanding of netrin-1 and its receptors in many inflammatory diseases and look forward to the bioavailability of netrin-1 for the future.
Topics: Carrier Proteins; Humans; Inflammation; Nerve Growth Factors; Netrin-1; Receptors, Cell Surface; Tumor Suppressor Proteins
PubMed: 35082104
DOI: 10.1016/j.cytogfr.2022.01.003 -
Nature Reviews. Neuroscience Mar 2023The midbrain dopamine (mDA) system is composed of molecularly and functionally distinct neuron subtypes that mediate specific behaviours and are linked to various brain... (Review)
Review
The midbrain dopamine (mDA) system is composed of molecularly and functionally distinct neuron subtypes that mediate specific behaviours and are linked to various brain diseases. Considerable progress has been made in identifying mDA neuron subtypes, and recent work has begun to unveil how these neuronal subtypes develop and organize into functional brain structures. This progress is important for further understanding the disparate physiological functions of mDA neurons and their selective vulnerability in disease, and will ultimately accelerate therapy development. This Review discusses recent advances in our understanding of molecularly defined mDA neuron subtypes and their circuits, ranging from early developmental events, such as neuron migration and axon guidance, to their wiring and function, and future implications for therapeutic strategies.
Topics: Humans; Dopaminergic Neurons; Mesencephalon; Brain; Dopamine; Brain Diseases
PubMed: 36653531
DOI: 10.1038/s41583-022-00669-3 -
Biochimica Et Biophysica Acta. Reviews... Nov 2022Recent studies have shown that peripheral nerves play an important role in the progression of breast cancer. Breast cancer cells (BCCs) promote local peripheral nerve... (Review)
Review
Recent studies have shown that peripheral nerves play an important role in the progression of breast cancer. Breast cancer cells (BCCs) promote local peripheral nerve growth and branching by secreting neuroactive molecules, including neurotrophins and axon guidance molecules (AGMs). Sympathetic nerves promote breast cancer progression, while parasympathetic and sensory nerves mainly have anti-tumor effects in the progression of breast cancer. Specifically, peripheral nerves can influence the progression of breast cancer by secreting neurotransmitters not only directly binding to the corresponding receptors of BCCs, but also indirectly acting on immune cells to modulate anti-tumor immunity. In this review, we summarize the crosstalk between breast cancer and peripheral nerves and the roles of important neuroactive molecules in the progression of breast cancer. In addition, we summarize indicators, including nerve fiber density and perineural invasion (PNI), that may help determine the prognosis of breast cancer based on current research results, as well as potential therapeutic approaches, such as β-blockers and retroviral-mediated genetic neuroengineering techniques, that may enhance the prognosis of breast cancer. In addition, we propose suggestions for future research priorities based on a current lack of knowledge in this area.
Topics: Humans; Female; Neoplasm Invasiveness; Breast Neoplasms; Axon Guidance; Peripheral Nervous System
PubMed: 36283598
DOI: 10.1016/j.bbcan.2022.188828 -
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 -
Cell Oct 2022Olfactory sensory neurons (OSNs) convert the stochastic choice of one of >1,000 olfactory receptor (OR) genes into precise and stereotyped axon targeting of OR-specific...
Olfactory sensory neurons (OSNs) convert the stochastic choice of one of >1,000 olfactory receptor (OR) genes into precise and stereotyped axon targeting of OR-specific glomeruli in the olfactory bulb. Here, we show that the PERK arm of the unfolded protein response (UPR) regulates both the glomerular coalescence of like axons and the specificity of their projections. Subtle differences in OR protein sequences lead to distinct patterns of endoplasmic reticulum (ER) stress during OSN development, converting OR identity into distinct gene expression signatures. We identify the transcription factor Ddit3 as a key effector of PERK signaling that maps OR-dependent ER stress patterns to the transcriptional regulation of axon guidance and cell-adhesion genes, instructing targeting precision. Our results extend the known functions of the UPR from a quality-control pathway that protects cells from misfolded proteins to a sensor of cellular identity that interprets physiological states to direct axon wiring.
Topics: Animals; Axons; Endoplasmic Reticulum Stress; Mice; Olfactory Bulb; Olfactory Receptor Neurons; Receptors, Odorant; Transcription Factors
PubMed: 36167070
DOI: 10.1016/j.cell.2022.08.025 -
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 -
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 -
International Journal of Molecular... May 2021How millions of axons navigate accurately toward synaptic targets during development is a long-standing question. Over decades, multiple studies have enriched our... (Review)
Review
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.
Topics: Animals; Axons; Glycoproteins; Glycosylation; Humans; Nerve Growth Factors; Signal Transduction
PubMed: 34068002
DOI: 10.3390/ijms22105143 -
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