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Investigative Ophthalmology & Visual... Jan 2021The three-dimensional configurations of rod and cone bipolar cell (BC) dendrites and horizontal cell (HC) processes outside rod and cone synaptic terminals have not been...
PURPOSE
The three-dimensional configurations of rod and cone bipolar cell (BC) dendrites and horizontal cell (HC) processes outside rod and cone synaptic terminals have not been fully elucidated. We reveal how these neurites are mutually arranged to coordinate formation and maintenance of the postsynaptic complex of ribbon synapses in mouse and monkey retinas.
METHODS
Serial section transmission electron microscopy was utilized to reconstruct BC and HC neurites in macaque monkey and mouse, including metabotropic glutamate receptor 6 (mGluR6)-knockout mice.
RESULTS
Starting from sporadically distributed branching points, rod BC and HC neurites (B and H, respectively) took specific paths to rod spherules by gradually adjusting their mutual positions, which resulted in a closed alternating pattern of H‒B‒H‒B neurites at the rod spherule aperture. This order corresponded to the array of elements constituting the postsynaptic complex of ribbon synapses. We identified novel helical coils of HC processes surrounding the rod BC dendrite in both mouse and macaque retinas, and these structures occurred more frequently in mGluR6-knockout than wild-type mouse retinas. Horizontal cell processes also formed hook-like protrusions that encircled cone BC and HC neurites below the cone pedicles in the macaque retina.
CONCLUSIONS
Bipolar and horizontal cell neurites take specific paths to adjust their mutual positions at the rod spherule aperture. Some HC processes are helically coiled around rod BC dendrites or form hook-like protrusions around cone BC dendrites and HC processes. Loss of mGluR6 signaling may be one factor promoting unbalanced neurite growth and compensatory neurite coiling.
Topics: Animals; Axon Fasciculation; Female; Macaca fuscata; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Neurites; Presynaptic Terminals; Receptors, Metabotropic Glutamate; Retinal Bipolar Cells; Retinal Horizontal Cells; Retinal Rod Photoreceptor Cells; Synapses; Visual Pathways
PubMed: 33507230
DOI: 10.1167/iovs.62.1.31 -
The Journal of Neuroscience : the... Jun 2019Selective cargo transport into axons and dendrites over the microtubule network is essential for neuron polarization. The axon initial segment (AIS) separates the axon...
Selective cargo transport into axons and dendrites over the microtubule network is essential for neuron polarization. The axon initial segment (AIS) separates the axon from the somatodendritic compartment and controls the microtubule-dependent transport into the axon. Interestingly, the AIS has a characteristic microtubule organization; it contains bundles of closely spaced microtubules with electron dense cross-bridges, referred to as microtubule fascicles. The microtubule binding protein TRIM46 localizes to the AIS and when overexpressed in non-neuronal cells forms microtubule arrays that closely resemble AIS fascicles in neurons. However, the precise role of TRIM46 in microtubule fasciculation in neurons has not been studied. Here we developed a novel correlative light and electron microscopy approach to study AIS microtubule organization. We show that in cultured rat hippocampal neurons of both sexes, TRIM46 levels steadily increase at the AIS during early neuronal differentiation and at the same time closely spaced microtubules form, whereas the fasciculated microtubules appear at later developmental stages. Moreover, we localized TRIM46 to the electron dense cross-bridges and show that depletion of TRIM46 causes loss of cross-bridges and increased microtubule spacing. These data indicate that TRIM46 has an essential role in organizing microtubule fascicles in the AIS. The axon initial segment (AIS) is a specialized region at the proximal axon where the action potential is initiated. In addition the AIS separates the axon from the somatodendritic compartment, where it controls protein transport to establish and maintain neuron polarity. Cargo vesicles destined for the axon recognize specialized microtubule tracks that enter the AIS. Interestingly the microtubules entering the AIS form crosslinked bundles, called microtubule fascicules. Recently we found that the microtubule-binding protein TRIM46 localizes to the AIS, where it may organize the AIS microtubules. In the present study we developed a novel correlative light and electron microscopy approach to study the AIS microtubules during neuron development and identified an essential role for TRIM46 in microtubule fasciculation.
Topics: Animals; Axon Fasciculation; Axon Initial Segment; Cell Polarity; Cells, Cultured; Cytoskeleton; Female; Hippocampus; Male; Microtubules; Neurons; Rats; Tripartite Motif Proteins
PubMed: 30967428
DOI: 10.1523/JNEUROSCI.3105-18.2019 -
The Neuroscientist : a Review Journal... Aug 2014Initially discovered as a potent neurite outgrowth inhibitor in the central nervous system (CNS), Nogo-A has emerged as a multifunctional protein. Involvement of this... (Review)
Review
Initially discovered as a potent neurite outgrowth inhibitor in the central nervous system (CNS), Nogo-A has emerged as a multifunctional protein. Involvement of this protein has been demonstrated in numerous developmental processes, ranging from cell migration, axon guidance and fasciculation, dendritic branching and CNS plasticity to oligodendrocyte differentiation and myelination. Although initially necessary and beneficial for shaping and later maintaining CNS structure and functionality, the growth restricting properties of Nogo-A can have negative effects on nervous system injury or disease. Hence, correlating with its various neurobiological roles, Nogo-A was implicated in a range of CNS disturbances, including trauma such as spinal cord injury or stroke, neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis or multiple sclerosis, or in schizophrenia. In this review, we summarize the current state of knowledge for Nogo-A's involvement in these nervous system diseases and perturbations and discuss the possible underlying mechanisms. Furthermore, we provide a comprehensive overview on molecular signaling pathways as well as structural properties identified for Nogo-A and point to open questions in the field.
PubMed: 24402613
DOI: 10.1177/1073858413516800 -
Scientific Reports Apr 2018Development of complex neural circuits like the peripheral somatosensory system requires intricate mechanisms to ensure axons make proper connections. While much is...
Development of complex neural circuits like the peripheral somatosensory system requires intricate mechanisms to ensure axons make proper connections. While much is known about ligand-receptor pairs required for dorsal root ganglion (DRG) axon guidance, very little is known about the cytoplasmic effectors that mediate cellular responses triggered by these guidance cues. Here we show that members of the Cas family of cytoplasmic signaling adaptors are highly phosphorylated in central projections of the DRG as they enter the spinal cord. Furthermore, we provide genetic evidence that Cas proteins regulate fasciculation of DRG sensory projections. These data establish an evolutionarily conserved requirement for Cas adaptor proteins during peripheral nervous system axon pathfinding. They also provide insight into the interplay between axonal fasciculation and adhesion to the substrate.
Topics: Animals; Axon Fasciculation; Crk-Associated Substrate Protein; Ganglia, Spinal; Gene Expression Regulation, Developmental; Mice; Phosphorylation; RNA, Messenger; Spinal Cord
PubMed: 29662228
DOI: 10.1038/s41598-018-24261-x -
Cerebral Cortex (New York, N.Y. : 1991) Jan 2021A better understanding of genetic influences on early white matter development could significantly advance our understanding of neurological and psychiatric conditions...
A better understanding of genetic influences on early white matter development could significantly advance our understanding of neurological and psychiatric conditions characterized by altered integrity of axonal pathways. We conducted a genome-wide association study (GWAS) of diffusion tensor imaging (DTI) phenotypes in 471 neonates. We used a hierarchical functional principal regression model (HFPRM) to perform joint analysis of 44 fiber bundles. HFPRM revealed a latent measure of white matter microstructure that explained approximately 50% of variation in our tractography-based measures and accounted for a large proportion of heritable variation in each individual bundle. An intronic SNP in PSMF1 on chromosome 20 exceeded the conventional GWAS threshold of 5 x 10-8 (p = 4.61 x 10-8). Additional loci nearing genome-wide significance were located near genes with known roles in axon growth and guidance, fasciculation, and myelination.
Topics: Axons; Chromosomes, Human, Pair 20; Diffusion Magnetic Resonance Imaging; Diffusion Tensor Imaging; Female; Genome-Wide Association Study; Humans; Image Processing, Computer-Assisted; Infant; Infant, Newborn; Male; Myelin Sheath; Nerve Fibers; Phenotype; Polymorphism, Single Nucleotide; Proteasome Endopeptidase Complex; Regression Analysis; White Matter
PubMed: 33009551
DOI: 10.1093/cercor/bhaa266 -
Frontiers in Neuroanatomy 2021Axon guidance proteins play key roles in the formation of neural circuits during development. We previously identified an axon guidance cue, named draxin, that has no... (Review)
Review
Axon guidance proteins play key roles in the formation of neural circuits during development. We previously identified an axon guidance cue, named draxin, that has no homology with other axon guidance proteins. Draxin is essential for the development of various neural circuits including the spinal cord commissure, corpus callosum, and thalamocortical projections. Draxin has been shown to not only control axon guidance through netrin-1 receptors, deleted in colorectal cancer (Dcc), and neogenin (Neo1) but also modulate netrin-1-mediated axon guidance and fasciculation. In this review, we summarize the multifaceted functions of draxin and netrin-1 signaling in neural circuit formation in the central nervous system. Furthermore, because recent studies suggest that the distributions and functions of axon guidance cues are highly regulated by glycoproteins such as Dystroglycan and Heparan sulfate proteoglycans, we discuss a possible function of glycoproteins in draxin/netrin-1-mediated axon guidance.
PubMed: 34899198
DOI: 10.3389/fnana.2021.766911 -
Cells Dec 2020During brain development, neurons need to form the correct connections with one another in order to give rise to a functional neuronal circuitry. Mistakes during this... (Review)
Review
During brain development, neurons need to form the correct connections with one another in order to give rise to a functional neuronal circuitry. Mistakes during this process, leading to the formation of improper neuronal connectivity, can result in a number of brain abnormalities and impairments collectively referred to as neurodevelopmental disorders. Cell adhesion molecules (CAMs), present on the cell surface, take part in the neurodevelopmental process regulating migration and recognition of specific cells to form functional neuronal assemblies. Among CAMs, the members of the protocadherin (PCDH) group stand out because they are involved in cell adhesion, neurite initiation and outgrowth, axon pathfinding and fasciculation, and synapse formation and stabilization. Given the critical role of these macromolecules in the major neurodevelopmental processes, it is not surprising that clinical and basic research in the past two decades has identified several genes as responsible for a large fraction of neurodevelopmental disorders. In the present article, we review these findings with a focus on the non-clustered PCDH sub-group, discussing the proteins implicated in the main neurodevelopmental disorders.
Topics: Amino Acid Motifs; Animals; Axons; Cadherins; Cell Adhesion; Cell Adhesion Molecules; Cell Movement; Cell Proliferation; Dendrites; Humans; Multigene Family; Mutation; Neurites; Neurodevelopmental Disorders; Neurogenesis; Neurons; Protein Isoforms; Protocadherins; Synapses; Tissue Distribution
PubMed: 33352832
DOI: 10.3390/cells9122711 -
PLoS Genetics Nov 2017Axon-guidance by Slit-Roundabout (Robo) signaling at the midline initially guides growth cones to synaptic targets and positions longitudinal axon tracts in discrete...
Axon-guidance by Slit-Roundabout (Robo) signaling at the midline initially guides growth cones to synaptic targets and positions longitudinal axon tracts in discrete bundles on either side of the midline. Following the formation of commissural tracts, Slit is found also in tracts of the commissures and longitudinal connectives, the purpose of which is not clear. The Slit protein is processed into a larger N-terminal peptide and a smaller C-terminal peptide. Here, I show that Slit and Slit-N in tracts interact with Robo to maintain the fasciculation, the inter-tract spacing between tracts and their position relative to the midline. Thus, in the absence of Slit in post-guidance tracts, tracts de-fasciculate, merge with one another and shift their position towards the midline. The Slit protein is proposed to function as a gradient. However, I show that Slit and Slit-N are not freely present in the extracellular milieu but associated with the extracellular matrix (ECM) and both interact with Robo1. Slit-C is tightly associated with the ECM requiring collagenase treatment to release it, and it does not interact with Robo1. These results define a role for Slit and Slit-N in tracts for the maintenance and fasciculation of tracts, thus the maintenance of the hardwiring of the CNS.
Topics: Animals; Axons; Drosophila; Drosophila Proteins; Extracellular Matrix; Fasciculation; Gene Expression Regulation, Developmental; Growth Cones; Nerve Tissue Proteins; Receptors, Immunologic; Signal Transduction; Spinal Cord; Roundabout Proteins
PubMed: 29155813
DOI: 10.1371/journal.pgen.1007094 -
Frontiers in Cellular Neuroscience 2024During the development of neural circuits, axons are guided by a variety of molecular cues to navigate through the brain and establish precise connections with correct...
During the development of neural circuits, axons are guided by a variety of molecular cues to navigate through the brain and establish precise connections with correct partners at the right time and place. Many axon guidance cues have been identified and they play pleiotropic roles in not only axon guidance but also axon fasciculation, axon pruning, and synaptogenesis as well as cell migration, angiogenesis, and bone formation. In search of receptors for Sema3E in axon guidance, we unexpectedly found that Plexin B3 is highly expressed in retinal ganglion cells of zebrafish embryos when retinal axons are crossing the midline to form the chiasm. Plexin B3 has been characterized to be related to neurodevelopmental disorders. However, the investigation of its pathological mechanisms is hampered by the lack of appropriate animal model. We provide evidence that Plexin B3 is critical for axon guidance . Plexin B3 might function as a receptor for Sema3E while Neuropilin1 could be a co-receptor. The intracellular domain of Plexin B3 is required for Semaphorin signaling transduction. Our data suggest that zebrafish could be an ideal animal model for investigating the role and mechanisms of Sema3E and Plexin B3 .
PubMed: 38628398
DOI: 10.3389/fncel.2024.1292969 -
Pathology International Feb 2015L1cam (L1), one of the cell adhesion molecules belonging to the immunoglobulin superfamily, plays critical roles in neuronal migration, axon growth, guidance,... (Review)
Review
L1cam (L1), one of the cell adhesion molecules belonging to the immunoglobulin superfamily, plays critical roles in neuronal migration, axon growth, guidance, fasciculation, and synaptic plasticity in the central as well as the peripheral nervous system. A number of X-linked forms of mental retardation have been associated with mutations in the L1 gene, including X-linked hydrocephalus in humans. Although model mice with different sites of L1 mutation have been studied, the pathogenetic mechanisms of hydrocephalus and mental retardation still remain unsolved. We herein present an overview of the function of L1 in the central nervous system and describe a human case of L1 mutation and knock-in mice that showed deleted sixth immunoglobulin of L1. Finally, we present experimental evidence showing that L1 is involved in murine neocortical histogenesis and propose a hypothetical mechanism of L1-linked hydrocephalus, with reference to corticogenesis.
Topics: Animals; Brain; Disease Models, Animal; Fetus; Humans; Hydrocephalus; Male; Mice; Neural Cell Adhesion Molecule L1; Neurogenesis; Stillbirth
PubMed: 25641508
DOI: 10.1111/pin.12245