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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 -
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 -
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 -
Progress in Neurobiology Mar 2021During the development of the nervous system, axons extend through complex environments. Growth cones at the axon tip allow axons to find and innervate their appropriate... (Review)
Review
During the development of the nervous system, axons extend through complex environments. Growth cones at the axon tip allow axons to find and innervate their appropriate targets and form functional synapses. Axon pathfinding requires axons to respond to guidance signals and these cues need to be detected by specialized receptors followed by intracellular signal integration and translation. Several downstream signaling pathways have been identified for axon guidance receptors and it has become evident that these pathways are often initiated from intracellular vesicles called endosomes. Endosomes allow receptors to traffic intracellularly, re-locating receptors from one cellular region to another. The localization of axon guidance receptors to endosomal compartments is crucial for their function, signaling output and expression levels. For example, active receptors within endosomes can recruit downstream proteins to the endosomal membrane and facilitate signaling. Also, endosomal trafficking can re-locate receptors back to the plasma membrane to allow re-activation or mediate downregulation of receptor signaling via degradation. Accumulating evidence suggests that axon guidance receptors do not follow a pre-set default trafficking route but may change their localization within endosomes. This re-routing appears to be spatially and temporally regulated, either by expression of adaptor proteins or co-receptors. These findings shed light on how signaling in axon guidance is regulated and diversified - a mechanism which explains how a limited set of guidance cues can help to establish billions of neuronal connections. In this review, we summarize and discuss our current knowledge of axon guidance receptor trafficking and provide directions for future research.
Topics: Axon Guidance; Axons; Endocytosis; Endosomes; Humans; Signal Transduction
PubMed: 32991957
DOI: 10.1016/j.pneurobio.2020.101916 -
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 -
Seminars in Cell & Developmental Biology Jan 2019The Drosophila motor system starts to assemble during embryonic development. It is composed of 30 muscles per abdominal hemisegment and 36 motor neurons assembling into... (Review)
Review
The Drosophila motor system starts to assemble during embryonic development. It is composed of 30 muscles per abdominal hemisegment and 36 motor neurons assembling into nerve branches to exit the CNS, navigate within the muscle field and finally establish specific connections with their target muscles. Several families of guidance molecules that play a role controlling this process as well as transcriptional regulators that program the behavior of specific motor neuron have been identified. In this review we summarize the role of both groups of molecules in the motor system as well as their relationship where known. It is apparent that partially redundant guidance protein families and membrane molecules with different functional output direct guidance decisions cooperatively. Some distinct transcriptional regulators seem to control guidance of specific nerve branches globally directing the expression of groups of pathfinding molecules in all motor neurons within the same motor branch.
Topics: Animals; Axon Guidance; Axons; Drosophila; Drosophila Proteins; Motor Neurons
PubMed: 29155221
DOI: 10.1016/j.semcdb.2017.11.013 -
Seminars in Cell & Developmental Biology Jan 2019Studies in the fruit fly Drosophila melanogaster have provided many fundamental insights into the genetic regulation of neural development, including the identification... (Review)
Review
Studies in the fruit fly Drosophila melanogaster have provided many fundamental insights into the genetic regulation of neural development, including the identification and characterization of evolutionarily conserved axon guidance pathways and their roles in important guidance decisions. Due to its highly organized and fast-developing embryonic nervous system, relatively small number of neurons, and molecular and genetic tools for identifying, labeling, and manipulating individual neurons or small neuronal subsets, studies of axon guidance in the Drosophila embryonic CNS have allowed researchers to dissect these genetic mechanisms with a high degree of precision. In this review, we discuss the major axon guidance pathways that regulate midline crossing of axons and the formation and guidance of longitudinal axon tracts, two processes that contribute to the development of the precise three-dimensional structure of the insect nerve cord. We focus particularly on recent insights into the roles and regulation of canonical midline axon guidance pathways, and on additional factors and pathways that have recently been shown to contribute to axon guidance decisions at and near the midline.
Topics: Animals; Axon Guidance; Axons; Central Nervous System; Drosophila
PubMed: 29174915
DOI: 10.1016/j.semcdb.2017.11.029 -
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 -
International Journal of Molecular... May 2020Neuronal axons are guided to their target during the development of the brain. Axon guidance allows the formation of intricate neural circuits that control the function... (Review)
Review
Neuronal axons are guided to their target during the development of the brain. Axon guidance allows the formation of intricate neural circuits that control the function of the brain, and thus the behavior. As the axons travel in the brain to find their target, they encounter various axon guidance cues, which interact with the receptors on the tip of the growth cone to permit growth along different signaling pathways. Although many scientists have performed numerous studies on axon guidance signaling pathways, we still have an incomplete understanding of the axon guidance system. Lately, studies on axon guidance have shifted from studying the signal transduction pathways to studying other molecular features of axon guidance, such as the gene expression. These new studies present evidence for different molecular features that broaden our understanding of axon guidance. Hence, in this review we will introduce recent studies that illustrate different molecular features of axon guidance. In particular, we will review literature that demonstrates how axon guidance cues and receptors regulate local translation of axonal genes and how the expression of guidance cues and receptors are regulated both transcriptionally and post-transcriptionally. Moreover, we will highlight the pathological relevance of axon guidance molecules to specific diseases.
Topics: Animals; Axon Guidance; Axons; Gene Expression Regulation; Humans; Protein Biosynthesis; RNA-Binding Proteins; Signal Transduction
PubMed: 32443632
DOI: 10.3390/ijms21103566