-
Current Biology : CB May 2019Building sensory dendritic arbors requires branching, growth, spacing, and substrate support. The conserved L1CAM family of cell-adhesion molecules generates neuronal...
Building sensory dendritic arbors requires branching, growth, spacing, and substrate support. The conserved L1CAM family of cell-adhesion molecules generates neuronal isoforms to regulate neurite development in various aspects. However, whether non-neuronal isoforms participate in any of these aspects is unclear. In Drosophila, the L1CAM homolog Neuroglian (Nrg) is expressed as two isoforms: the neuronal isoform Nrg180 on dendritic surfaces of dendritic arborization (da) neurons and the non-neuronal isoform Nrg167 in epidermis innervated by dendrites. We found that epidermal Nrg167 encircles dendrites by interactions with dendritic Nrg180 to support dendrite growth, stabilization, and enclosure inside epidermis. Interestingly, whereas Nrg180 forms homophilic interactions to facilitate axonal bundling, heteroneuronal dendrites in the same innervating field avoid bundling through unknown mechanisms to maintain individual dendritic patterns. Here, we show that both epidermal Nrg167 depletion and neuronal Nrg180 overexpression can cause dendrite bundling, with genetic analyses suggesting that Nrg167-Nrg180 interactions antagonize Nrg180-Nrg180 homophilic interaction to prevent dendrite bundling. Furthermore, internalization of Nrg180 also participates in resolving dendrite bundling, as overexpression of endocytosis-defective Nrg180 and compromising endocytosis in neurons both exacerbated dendrite-bundling defects. Together, our study highlights the functional significance of substrate-derived Nrg167 in conferring dendrite stability, positioning, and avoidance.
Topics: Animals; Cell Adhesion Molecules, Neuronal; Cell Line; Dendrites; Drosophila Proteins; Drosophila melanogaster; Protein Isoforms
PubMed: 31006568
DOI: 10.1016/j.cub.2019.03.050 -
The Journal of Neuroscience : the... Nov 2018Neurons of the CNS elaborate highly branched dendritic arbors that host numerous dendritic spines, which serve as the postsynaptic platform for most excitatory synapses....
Neurons of the CNS elaborate highly branched dendritic arbors that host numerous dendritic spines, which serve as the postsynaptic platform for most excitatory synapses. The actin cytoskeleton plays an important role in dendrite development and spine formation, but the underlying mechanisms remain incompletely understood. Tropomodulins (Tmods) are a family of actin-binding proteins that cap the slow-growing (pointed) end of actin filaments, thereby regulating the stability, length, and architecture of complex actin networks in diverse cell types. Three members of the Tmod family, Tmod1, Tmod2, and Tmod3 are expressed in the vertebrate CNS, but their function in neuronal development is largely unknown. In this study, we present evidence that Tmod1 and Tmod2 exhibit distinct roles in regulating spine development and dendritic arborization, respectively. Using rat hippocampal tissues from both sexes, we find that Tmod1 and Tmod2 are expressed with distinct developmental profiles: Tmod2 is expressed early during hippocampal development, whereas Tmod1 expression coincides with synaptogenesis. We then show that knockdown of Tmod2, but not Tmod1, severely impairs dendritic branching. Both Tmod1 and Tmod2 are localized to a distinct subspine region where they regulate local F-actin stability. However, the knockdown of Tmod1, but not Tmod2, disrupts spine morphogenesis and impairs synapse formation. Collectively, these findings demonstrate that regulation of the actin cytoskeleton by different members of the Tmod family plays an important role in distinct aspects of dendrite and spine development. The Tropomodulin family of molecules is best known for controlling the length and stability of actin myofilaments in skeletal muscles. While several Tropomodulin members are expressed in the brain, fundamental knowledge about their role in neuronal function is limited. In this study, we show the unique expression profile and subcellular distribution of Tmod1 and Tmod2 in hippocampal neurons. While both Tmod1 and Tmod2 regulate F-actin stability, we find that they exhibit isoform-specific roles in dendrite development and synapse formation: Tmod2 regulates dendritic arborization, whereas Tmod1 is required for spine development and synapse formation. These findings provide novel insight into the actin regulatory mechanisms underlying neuronal development, thereby shedding light on potential pathways disrupted in a number of neurological disorders.
Topics: Animals; Cells, Cultured; Dendrites; Female; Hippocampus; Male; Neurons; Pregnancy; Protein Isoforms; Rats; Rats, Sprague-Dawley; Synapses; Tropomodulin
PubMed: 30301754
DOI: 10.1523/JNEUROSCI.3325-17.2018 -
Scientific Reports May 2022We present a new computational framework of neuron growth based on the phase field method and develop an open-source software package called...
We present a new computational framework of neuron growth based on the phase field method and develop an open-source software package called "NeuronGrowth_IGAcollocation". Neurons consist of a cell body, dendrites, and axons. Axons and dendrites are long processes extending from the cell body and enabling information transfer to and from other neurons. There is high variation in neuron morphology based on their location and function, thus increasing the complexity in mathematical modeling of neuron growth. In this paper, we propose a novel phase field model with isogeometric collocation to simulate different stages of neuron growth by considering the effect of tubulin. The stages modeled include lamellipodia formation, initial neurite outgrowth, axon differentiation, and dendrite formation considering the effect of intracellular transport of tubulin on neurite outgrowth. Through comparison with experimental observations, we can demonstrate qualitatively and quantitatively similar reproduction of neuron morphologies at different stages of growth and allow extension towards the formation of neurite networks.
Topics: Axons; Dendrites; Neurites; Neurogenesis; Neurons; Tubulin
PubMed: 35581253
DOI: 10.1038/s41598-022-12073-z -
Cell Feb 2020The mystery of general anesthesia is that it specifically suppresses consciousness by disrupting feedback signaling in the brain, even when feedforward signaling and...
The mystery of general anesthesia is that it specifically suppresses consciousness by disrupting feedback signaling in the brain, even when feedforward signaling and basic neuronal function are left relatively unchanged. The mechanism for such selectiveness is unknown. Here we show that three different anesthetics have the same disruptive influence on signaling along apical dendrites in cortical layer 5 pyramidal neurons in mice. We found that optogenetic depolarization of the distal apical dendrites caused robust spiking at the cell body under awake conditions that was blocked by anesthesia. Moreover, we found that blocking metabotropic glutamate and cholinergic receptors had the same effect on apical dendrite decoupling as anesthesia or inactivation of the higher-order thalamus. If feedback signaling occurs predominantly through apical dendrites, the cellular mechanism we found would explain not only how anesthesia selectively blocks this signaling but also why conscious perception depends on both cortico-cortical and thalamo-cortical connectivity.
Topics: Anesthetics, General; Animals; Cerebral Cortex; Cholinergic Antagonists; Consciousness; Dendrites; Excitatory Amino Acid Antagonists; Feedback, Physiological; Female; Male; Mice; Pyramidal Cells; Synaptic Transmission; Thalamus
PubMed: 32084339
DOI: 10.1016/j.cell.2020.01.024 -
Developmental Biology Jun 2022Many neurons in bilaterian animals are polarized with functionally distinct axons and dendrites. Microtubule polarity, microtubule stability, and the axon initial...
Many neurons in bilaterian animals are polarized with functionally distinct axons and dendrites. Microtubule polarity, microtubule stability, and the axon initial segment (AIS) have all been shown to influence polarized transport in neurons. Each of these cytoskeletal cues could act independently to control axon and dendrite identity, or there could be a hierarchy in which one acts upstream of the others. Here we test the hypothesis that microtubule polarity acts as a master regulator of neuronal polarity by using a Drosophila genetic background in which some dendrites have normal minus-end-out microtubule polarity and others have the axonal plus-end-out polarity. In these mosaic dendrite arbors, we found that ribosomes, which are more abundant in dendrites than axons, were reduced in plus-end-out dendrites, while an axonal cargo was increased. In addition, we determined that microtubule stability was different in plus-end-out and minus-end-out dendrites, with plus-end-out ones having more stable microtubules like axons. Similarly, we found that ectopic diffusion barriers, like those at the AIS, formed at the base of dendrites with plus-end-out regions. Thus, changes in microtubule polarity were sufficient to rearrange other cytoskeletal features associated with neuronal polarization. However, overall neuron shape was maintained with only subtle changes in branching in mosaic arbors. We conclude that microtubule polarity can act upstream of many aspects of intracellular neuronal polarization, but shape is relatively resilient to changes in microtubule polarity in vivo.
Topics: Animals; Axons; Cell Polarity; Dendrites; Drosophila; Microtubules; Neurons
PubMed: 35341730
DOI: 10.1016/j.ydbio.2022.03.009 -
ENeuro 2022Dendritic spines have diverse morphologies, with a wide range of head and neck sizes, and these morphologic differences likely generate different functional properties....
Dendritic spines have diverse morphologies, with a wide range of head and neck sizes, and these morphologic differences likely generate different functional properties. To explore how this morphologic diversity differs across species and ages we analyzed 3D confocal reconstructions of ∼8000 human spines and ∼1700 mouse spines, labeled by intracellular injections in fixed tissue. Using unsupervised algorithms, we computationally separated spine heads and necks and systematically measured morphologic features of spines in apical and basal dendrites from cortical pyramidal cells. Human spines had unimodal distributions of parameters, without any evidence of morphologic subtypes. Their spine necks were longer and thinner in apical than in basal spines, and spine head volumes of an 85-year-old individual were larger than those of a 40-year-old individual. Human spines had longer and thicker necks and larger head volumes than mouse spines. Our results indicate that human spines form part of a continuum, are larger and longer than those of mice, and become larger with increasing adult age. These morphologic differences in spines across species could generate functional differences in biochemical and electrical spine compartmentalization, or in synaptic properties, across species and ages.
Topics: Animals; Dendrites; Dendritic Spines; Humans; Mice; Pyramidal Cells
PubMed: 35610025
DOI: 10.1523/ENEURO.0039-22.2022 -
Neuroscience Bulletin Aug 2014A typical neuron is comprised of an information input compartment, or the dendrites, and an output compartment, known as the axon. These two compartments are the... (Review)
Review
A typical neuron is comprised of an information input compartment, or the dendrites, and an output compartment, known as the axon. These two compartments are the structural basis for functional neural circuits. However, little is known about how dendritic and axonal growth are differentially regulated. Recent studies have uncovered two distinct types of regulatory mechanisms that differentiate dendritic and axonal growth: dedicated mechanisms and bimodal mechanisms. Dedicated mechanisms regulate either dendritespecific or axon-specific growth; in contrast, bimodal mechanisms direct dendritic and axonal development in opposite manners. Here, we review the dedicated and bimodal regulators identified by recent Drosophila and mammalian studies. The knowledge of these underlying molecular mechanisms not only expands our understanding about how neural circuits are wired, but also provides insights that will aid in the rational design of therapies for neurological diseases.
Topics: Animals; Axons; Dendrites; Drosophila; Drosophila Proteins; Humans; Intercellular Signaling Peptides and Proteins; Transcription Factors
PubMed: 25001617
DOI: 10.1007/s12264-014-1447-3 -
Trends in Neurosciences Feb 2017Although the importance of network connectivity is increasingly recognized, identifying synapses remains challenging relative to the routine characterization of neuronal... (Review)
Review
Although the importance of network connectivity is increasingly recognized, identifying synapses remains challenging relative to the routine characterization of neuronal morphology. Thus, researchers frequently employ axon-dendrite colocations as proxies of potential connections. This putative equivalence, commonly referred to as Peters' rule, has been recently studied at multiple levels and scales, fueling passionate debates regarding its validity. Our critical literature review identifies three conceptually distinct but often confused applications: inferring neuron type circuitry, predicting synaptic contacts among individual cells, and estimating synapse numbers within neuron pairs. Paradoxically, at the originally proposed cell-type level, Peters' rule remains largely untested. Leveraging Hippocampome.org, we validate and refine the relationship between axonal-dendritic colocations and synaptic circuits, clarifying the interpretation of existing and forthcoming data.
Topics: Animals; Axons; Dendrites; Humans; Nerve Net; Neurons; Synapses; Time Factors
PubMed: 28041634
DOI: 10.1016/j.tins.2016.11.007 -
Molecular Biology of the Cell Oct 2023Nervous systems exhibit dramatic diversity in cell morphology and size. How neurons regulate their biosynthetic and secretory machinery to support such diversity is not...
Nervous systems exhibit dramatic diversity in cell morphology and size. How neurons regulate their biosynthetic and secretory machinery to support such diversity is not well understood. Endoplasmic reticulum exit sites (ERESs) are essential for maintaining secretory flux, and are required for normal dendrite development, but how neurons of different size regulate secretory capacity remains unknown. In , we find that the ERES number is strongly correlated with the size of a neuron's dendritic arbor. The elaborately branched sensory neuron, PVD, has especially high ERES numbers. Asymmetric cell division provides PVD with a large initial cell size critical for rapid establishment of PVD's high ERES number before neurite outgrowth, and these ERESs are maintained throughout development. Maintenance of ERES number requires the cell fate transcription factor MEC-3, TOR (), and nutrient availability, with and mutant PVDs both displaying reductions in ERES number, soma size, and dendrite size. Notably, mutant animals exhibit reduced expression of a reporter in PVD, and starvation reduces ERES number and somato-dendritic size in a manner genetically redundant with perturbation. Our data suggest that both asymmetric cell division and nutrient sensing pathways regulate secretory capacities to support elaborate dendritic arbors.
Topics: Animals; Caenorhabditis elegans; Sensory Receptor Cells; Caenorhabditis elegans Proteins; Biological Transport; Endoplasmic Reticulum; Dendrites
PubMed: 37556208
DOI: 10.1091/mbc.E23-03-0090 -
Molecular Neurobiology Mar 2019Glial cells and neuronal dendrites were historically assumed to be passive structures that play only supportive physiological roles, with no active contribution to... (Review)
Review
Glial cells and neuronal dendrites were historically assumed to be passive structures that play only supportive physiological roles, with no active contribution to information processing in the central nervous system. Research spanning the past few decades has clearly established this assumption to be far from physiological realities. Whereas the discovery of active channel conductances and their localized plasticity was the turning point for dendritic structures, the demonstration that glial cells release transmitter molecules and communicate across the neuroglia syncytium through calcium wave propagation constituted path-breaking discoveries for glial cell physiology. An additional commonality between these two structures is the ability of calcium stores within their endoplasmic reticulum (ER) to support active propagation of calcium waves, which play crucial roles in the spatiotemporal integration of information within and across cells. Although there have been several demonstrations of regulatory roles of glial cells and dendritic structures in achieving common physiological goals such as information propagation and adaptability through plasticity, studies assessing physiological interactions between these two active structures have been few and far. This lacuna is especially striking given the strong connectivity that is known to exist between these two structures through several complex and tightly intercoupled mechanisms that also recruit their respective ER structures. In this review, we present brief overviews of the parallel literatures on active dendrites and active glial physiology and make a strong case for future studies to directly assess the strong interactions between these two structures in regulating physiology and pathophysiology of the brain.
Topics: Animals; Brain; Calcium Signaling; Dendrites; Humans; Neuroglia; Neuronal Plasticity; Neurons
PubMed: 30014322
DOI: 10.1007/s12035-018-1223-5