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The Journal of Neuroscience : the... Oct 2015Neurons typically assume multipolar, bipolar, or unipolar morphologies. Little is known about the mechanisms underlying the development of these basic morphological...
UNLABELLED
Neurons typically assume multipolar, bipolar, or unipolar morphologies. Little is known about the mechanisms underlying the development of these basic morphological types. Here, we show that the Krüppel-like transcription factor Dar1 determines the multipolar morphology of postmitotic neurons in Drosophila. Dar1 is specifically expressed in multipolar neurons and loss of dar1 gradually converts multipolar neurons into the bipolar or unipolar morphology without changing neuronal identity. Conversely, misexpression of Dar1 or its mammalian homolog in unipolar and bipolar neurons causes them to assume multipolar morphologies. Dar1 regulates the expression of several dynein genes and nuclear distribution protein C (nudC), which is an essential component of a specialized dynein complex that positions the nucleus in a cell. We further show that these genes are required for Dar1-induced multipolar neuron morphology. Dar1 likely functions as a terminal selector gene for the basic layout of neuron morphology by regulating both dendrite extension and the dendrite-nucleus coupling.
SIGNIFICANCE STATEMENT
The three basic morphological types of neurons--unipolar, bipolar, and multipolar--are important for information processing and wiring of neural circuits. Little progress has been made toward understanding the molecular and cellular programs that generate these types since their discovery over a century ago. It is generally assumed that basic morphological types of neurons are determined by the number of dendrites growing out from the cell body. Here, we show that this model alone is insufficient. We introduce the positioning of nucleus as a critical factor in this process and report that the transcription factor Dar1 determines multipolar neuron morphology in postmitotic neurons by regulating genes involved in nuclear positioning.
Topics: Animals; Animals, Genetically Modified; Cell Cycle; Drosophila; Drosophila Proteins; Dyneins; Gene Expression Regulation, Developmental; Green Fluorescent Proteins; Microscopy, Confocal; Neurons; Peripheral Nerves; RNA Interference; RNA, Messenger; Receptors, G-Protein-Coupled; Receptors, Neuropeptide
PubMed: 26490864
DOI: 10.1523/JNEUROSCI.1610-15.2015 -
Development (Cambridge, England) Jun 2015Neurons are highly polarized cells with structurally and functionally distinct processes called axons and dendrites. This polarization underlies the directional flow of... (Review)
Review
Neurons are highly polarized cells with structurally and functionally distinct processes called axons and dendrites. This polarization underlies the directional flow of information in the central nervous system, so the establishment and maintenance of neuronal polarization is crucial for correct development and function. Great progress in our understanding of how neurons establish their polarity has been made through the use of cultured hippocampal neurons, while recent technological advances have enabled in vivo analysis of axon specification and elongation. This short review and accompanying poster highlight recent advances in this fascinating field, with an emphasis on the signaling mechanisms underlying axon and dendrite specification in vitro and in vivo.
Topics: Animals; Axons; Brain; Cell Polarity; Dendrites; Humans; Mice; Neurons; Signal Transduction; rho GTP-Binding Proteins
PubMed: 26081570
DOI: 10.1242/dev.114454 -
Trends in Neurosciences Jul 2006The genetic basis is now known for several disorders of neuronal migration in the developing cerebral cortex. Identification of the cellular processes mediated by the... (Review)
Review
The genetic basis is now known for several disorders of neuronal migration in the developing cerebral cortex. Identification of the cellular processes mediated by the implicated genes is revealing crucial stages of neuronal migration and has the potential to reveal common cellular causes of neuronal migration disorders. We hypothesize that a newly recognized morphological stage of neuronal migration, the multipolar stage, is vulnerable and is disrupted in several disorders of neocortical development. The multipolar stage occurs as bipolar progenitor cells become radially migrating neurons. Several studies using in utero electroporation and RNAi have revealed that transition out of the multipolar stage depends on the function of filamin A, LIS1 and DCX. Mutations in the genes encoding these proteins in humans cause distinct neuronal migration disorders, including periventricular nodular heterotopia, subcortical band heterotopia and lissencephaly. The multipolar stage therefore seems to be a critical point of migration control and a vulnerable target for disruption of neocortical development. This review is part of the INMED/TINS special issue "Nature and nurture in brain development and neurological disorders", based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).
Topics: Animals; Cell Movement; Cerebral Cortex; Doublecortin Domain Proteins; Doublecortin Protein; Microtubule-Associated Proteins; Models, Biological; Nervous System Malformations; Neurons; Neuropeptides
PubMed: 16713637
DOI: 10.1016/j.tins.2006.05.006 -
Nature Reviews. Neuroscience Sep 2013Like all cells, neurons are made of proteins that have characteristic synthesis and degradation profiles. Unlike other cells, however, neurons have a unique multipolar... (Review)
Review
Like all cells, neurons are made of proteins that have characteristic synthesis and degradation profiles. Unlike other cells, however, neurons have a unique multipolar architecture that makes ∼10,000 synaptic contacts with other neurons. Both the stability and modifiability of the neuronal proteome are crucial for its information-processing, storage and plastic properties. The cell biological mechanisms that synthesize, modify, deliver and degrade dendritic and synaptic proteins are not well understood but appear to reflect unique solutions adapted to the particular morphology of neurons.
Topics: Animals; Cell Compartmentation; Dendrites; Humans; Nerve Tissue Proteins; Neurons; Prions; Synapses
PubMed: 23900412
DOI: 10.1038/nrn3546 -
Journal of Anatomy Jun 1994The morphology and synaptic organisation of a type of multipolar neuron of the lizard cerebral cortex were studied by Golgi impregnation, intracellular injection of...
The morphology and synaptic organisation of a type of multipolar neuron of the lizard cerebral cortex were studied by Golgi impregnation, intracellular injection of horseradish peroxidase, electron microscopy, and immunocytochemistry. It is a GABA-immunoreactive interneuron and most likely parvalbumin-immunoreactive. Its conspicuous axonal arbor is characterised by an initial segment arising from the soma or from a juxtasomatic dendritic segment. The initial axon segment ramifies and gives rise to thick myelinated segments that terminate in short unmyelinated branches studded with thick boutons 'en passant' that (1) make axosomatic synapses on bipyramidal neuronal somata and (2) synapse on initial apical dendritic segments of bipyramidal neurons forming climbing-like cartridges. The dendrites extend throughout the thickness of the cortex, receiving synaptic input from a variety of sources of which the most prominent is that of zinc-positive boutons coming from granule cells of the medial cortex. According to its synaptology, this interneuron may play a role in regulating the activity of bipyramidal neurons by both feed-forward and feed-back inhibition mechanisms. From a comparative standpoint, it may be related to the sparsely spiny or nonspiny multipolar neurons of the stratum oriens of the mammalian hippocampus.
Topics: Animals; Cerebral Cortex; Female; Immunohistochemistry; Lizards; Male; Microscopy, Electron; Neurons
PubMed: 7928645
DOI: No ID Found -
Current Opinion in Cell Biology Aug 2012In a biological sense, polarity refers to the extremity of the main axis of an organelle, cell, or organism. In neurons, morphological polarity begins with the... (Review)
Review
In a biological sense, polarity refers to the extremity of the main axis of an organelle, cell, or organism. In neurons, morphological polarity begins with the appearance of the first neurite from the cell body. In multipolar neurons, a second phase of polarization occurs when a single neurite initiates a phase of rapid growth to become the neuron's axon, while the others later differentiate as dendrites. Finally, during a third phase, axons and dendrites develop an elaborate architecture, acquiring special morphological and molecular features that commit them to their final identities. Mechanistically, each phase must be preceded by spatial restriction of growth activity. We will review recent work on the mechanisms underlying the polarized growth of neurons.
Topics: Cell Polarity; Neurites; Neurons; Organelles
PubMed: 22726583
DOI: 10.1016/j.ceb.2012.05.011 -
Neuron Jun 2012Pyramidal cells of the cerebral cortex are born in the ventricular zone and migrate through the intermediate zone to enter into the cortical plate. In the intermediate...
Pyramidal cells of the cerebral cortex are born in the ventricular zone and migrate through the intermediate zone to enter into the cortical plate. In the intermediate zone, these migrating precursors move tangentially and initiate the extension of their axons by transiently adopting a characteristic multipolar morphology. We observe that expression of the forkhead transcription factor FoxG1 is dynamically regulated during this transitional period. By utilizing conditional genetic strategies, we show that the downregulation of FoxG1 at the beginning of the multipolar cell phase induces Unc5D expression, the timing of which ultimately determines the laminar identity of pyramidal neurons. In addition, we demonstrate that the re-expression of FoxG1 is required for cells to transit out of the multipolar cell phase and to enter into the cortical plate. Thus, the dynamic expression of FoxG1 during migration within the intermediate zone is essential for the proper assembly of the cerebral cortex.
Topics: Animals; Cell Movement; Cerebral Cortex; Forkhead Transcription Factors; Gene Expression Regulation, Developmental; Mice; Nerve Tissue Proteins; Pyramidal Cells
PubMed: 22726835
DOI: 10.1016/j.neuron.2012.04.025 -
The Journal of Neuroscience : the... Jan 2023In the developing cortex, excitatory neurons migrate along the radial fibers to their final destinations and build up synaptic connection with each other to form...
In the developing cortex, excitatory neurons migrate along the radial fibers to their final destinations and build up synaptic connection with each other to form functional circuitry. The shaping of neuronal morphologies by actin cytoskeleton dynamics is crucial for neuronal migration. However, it is largely unknown how the distribution and assembly of the F-actin cytoskeleton are coordinated. In the present study, we found that an actin regulatory protein, coronin 2B, is indispensable for the transition from a multipolar to bipolar morphology during neuronal migration in ICR mice of either sex. Loss of coronin 2B led to heterotopic accumulation of migrating neurons in the intermediate zone along with reduced dendritic complexity and aberrant neuronal activity in the cortical plate. This was accompanied by increased seizure susceptibility, suggesting the malfunction of cortical development in coronin 2B-deficient brains. Coronin 2B knockdown disrupted the distribution of the F-actin cytoskeleton at the leading processes, while the migration defect in coronin 2B-deficient neurons was partially rescued by overexpression of Rac1 and its downstream actin-severing protein, cofilin. Our results collectively reveal the physiological function of coronin 2B during neuronal migration whereby it maintains the proper distribution of activated Rac1 and the F-actin cytoskeleton. Deficits in neuronal migration during cortical development result in various neurodevelopmental disorders (e.g., focal cortical dysplasia, periventricular heterotopia, epilepsy, etc.). Most signaling pathways that control neuronal migration process converge to regulate actin cytoskeleton dynamics. Therefore, it is important to understand how actin dynamics is coordinated in the critical processes of neuronal migration. Herein, we report that coronin 2B is a key protein that regulates neuronal migration through its ability to control the distribution of the actin cytoskeleton and its regulatory signaling protein Rac1 during the multipolar-bipolar transition in the intermediate zone, providing insights into the molecular machinery that drives the migration process of newborn neurons.
Topics: Animals; Mice; Actins; Cell Movement; Mice, Inbred ICR; Microfilament Proteins; rac1 GTP-Binding Protein; Neurons
PubMed: 36639906
DOI: 10.1523/JNEUROSCI.1087-22.2022 -
ELife Oct 2019The functions of FGF receptors (FGFRs) in early development of the cerebral cortex are well established. Their functions in the migration of neocortical projection...
The functions of FGF receptors (FGFRs) in early development of the cerebral cortex are well established. Their functions in the migration of neocortical projection neurons, however, are unclear. We have found that FGFRs regulate multipolar neuron orientation and the morphological change into bipolar cells necessary to enter the cortical plate. Mechanistically, our results suggest that FGFRs are activated by N-Cadherin. N-Cadherin cell-autonomously binds FGFRs and inhibits FGFR K27- and K29-linked polyubiquitination and lysosomal degradation. Accordingly, FGFRs accumulate and stimulate prolonged Erk1/2 phosphorylation. Neurons inhibited for Erk1/2 are stalled in the multipolar zone. Moreover, Reelin, a secreted protein regulating neuronal positioning, prevents FGFR degradation through N-Cadherin, causing Erk1/2 phosphorylation. These findings reveal novel functions for FGFRs in cortical projection neuron migration, suggest a physiological role for FGFR and N-Cadherin interaction in vivo and identify Reelin as an extracellular upstream regulator and Erk1/2 as downstream effectors of FGFRs during neuron migration.
Topics: Animals; Cadherins; Cell Adhesion Molecules, Neuronal; Extracellular Matrix Proteins; MAP Kinase Signaling System; Mice; Neocortex; Nerve Tissue Proteins; Neurogenesis; Neurons; Phosphorylation; Receptors, Fibroblast Growth Factor; Reelin Protein; Serine Endopeptidases; Ubiquitination
PubMed: 31577229
DOI: 10.7554/eLife.47673 -
Neuroscience Research Sep 2021The principal olivary nucleus is the largest part of the inferior olivary complex and is involved in the spatial and temporal organization of movement and motor...
The principal olivary nucleus is the largest part of the inferior olivary complex and is involved in the spatial and temporal organization of movement and motor learning. Nearly all neurons in this nucleus is multipolar along with having a highly complex dendritic tree and significant asymmetry in shape. In this study, we updated the current classification scheme, examined morphological differences between the proposed groups, and investigated age-related morphological changes. Histological preparations were digitized by a light microscope and a sample of 259 images of neurons was analyzed by 17 computationally generated parameters of morphology. These were reduced to the four variables of principal component analysis and the sample was classified by k-means method of clustering into three clusters. The differences between clusters were documented and for medium-sized neurons the relationship between four morphological parameters and age were investigated. Finally, for two of the age groups the changes in the morphology were explored. This study includes a detailed and robust classification of the PON neurons and the findings improve upon past qualitative work.
Topics: Humans; Neurons; Olivary Nucleus
PubMed: 33347909
DOI: 10.1016/j.neures.2020.10.005