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Epidermal Growth Factor Signaling Promotes Sleep through a Combined Series and Parallel Neural Circuit.
Konietzka J, Fritz M, Spiri S, McWhirter R, Leha A, Palumbos S, Costa WS, Oranth A, Gottschalk A, Miller DM, Hajnal A, Bringmann H
(2020) Curr Biol 30: 1-16.e13
MeSH Terms: Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Epidermal Growth Factor, Neurons, Signal Transduction, Sleep
Show Abstract · Added March 3, 2020
Sleep requires sleep-active neurons that depolarize to inhibit wake circuits. Sleep-active neurons are under the control of homeostatic mechanisms that determine sleep need. However, little is known about the molecular and circuit mechanisms that translate sleep need into the depolarization of sleep-active neurons. During many stages and conditions in C. elegans, sleep requires a sleep-active neuron called RIS. Here, we defined the transcriptome of RIS and discovered that genes of the epidermal growth factor receptor (EGFR) signaling pathway are expressed in RIS. Because of cellular stress, EGFR directly activates RIS. Activation of EGFR signaling in the ALA neuron has previously been suggested to promote sleep independently of RIS. Unexpectedly, we found that ALA activation promotes RIS depolarization. Our results suggest that ALA is a drowsiness neuron with two separable functions: (1) it inhibits specific behaviors, such as feeding, independently of RIS, (2) and it activates RIS. Whereas ALA plays a strong role in surviving cellular stress, surprisingly, RIS does not. In summary, EGFR signaling can depolarize RIS by an indirect mechanism through activation of the ALA neuron that acts upstream of the sleep-active RIS neuron and through a direct mechanism using EGFR signaling in RIS. ALA-dependent drowsiness, rather than RIS-dependent sleep bouts, appears to be important for increasing survival after cellular stress, suggesting that different types of behavioral inhibition play different roles in restoring health. VIDEO ABSTRACT.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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7 MeSH Terms
neurons have functional dendritic spines.
Cuentas-Condori A, Mulcahy B, He S, Palumbos S, Zhen M, Miller DM
(2019) Elife 8:
MeSH Terms: Animals, Caenorhabditis elegans, Dendritic Spines, Intravital Microscopy, Microscopy, Electron, Microscopy, Fluorescence, Motor Neurons, Organelles
Show Abstract · Added March 3, 2020
Dendritic spines are specialized postsynaptic structures that transduce presynaptic signals, are regulated by neural activity and correlated with learning and memory. Most studies of spine function have focused on the mammalian nervous system. However, spine-like protrusions have been reported in (Philbrook et al., 2018), suggesting that the experimental advantages of smaller model organisms could be exploited to study the biology of dendritic spines. Here, we used super-resolution microscopy, electron microscopy, live-cell imaging and genetics to show that motor neurons have functional dendritic spines that: (1) are structurally defined by a dynamic actin cytoskeleton; (2) appose presynaptic dense projections; (3) localize ER and ribosomes; (4) display calcium transients triggered by presynaptic activity and propagated by internal Ca stores; (5) respond to activity-dependent signals that regulate spine density. These studies provide a solid foundation for a new experimental paradigm that exploits the power of genetics and live-cell imaging for fundamental studies of dendritic spine morphogenesis and function.
© 2019, Cuentas-Condori et al.
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8 MeSH Terms
Actin assembly and non-muscle myosin activity drive dendrite retraction in an UNC-6/Netrin dependent self-avoidance response.
Sundararajan L, Smith CJ, Watson JD, Millis BA, Tyska MJ, Miller DM
(2019) PLoS Genet 15: e1008228
MeSH Terms: Actin Cytoskeleton, Actin-Related Protein 2-3 Complex, Actins, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Dendritic Cells, Membrane Proteins, Myosin Heavy Chains, Nerve Tissue Proteins, Netrins, Neurons, Nonmuscle Myosin Type IIB
Show Abstract · Added March 3, 2020
Dendrite growth is constrained by a self-avoidance response that induces retraction but the downstream pathways that balance these opposing mechanisms are unknown. We have proposed that the diffusible cue UNC-6(Netrin) is captured by UNC-40(DCC) for a short-range interaction with UNC-5 to trigger self-avoidance in the C. elegans PVD neuron. Here we report that the actin-polymerizing proteins UNC-34(Ena/VASP), WSP-1(WASP), UNC-73(Trio), MIG-10(Lamellipodin) and the Arp2/3 complex effect dendrite retraction in the self-avoidance response mediated by UNC-6(Netrin). The paradoxical idea that actin polymerization results in shorter rather than longer dendrites is explained by our finding that NMY-1 (non-muscle myosin II) is necessary for retraction and could therefore mediate this effect in a contractile mechanism. Our results also show that dendrite length is determined by the antagonistic effects on the actin cytoskeleton of separate sets of effectors for retraction mediated by UNC-6(Netrin) versus outgrowth promoted by the DMA-1 receptor. Thus, our findings suggest that the dendrite length depends on an intrinsic mechanism that balances distinct modes of actin assembly for growth versus retraction.
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MeSH Terms
Mechanisms that regulate morphogenesis of a highly branched neuron in C. elegans.
Sundararajan L, Stern J, Miller DM
(2019) Dev Biol 451: 53-67
MeSH Terms: Animals, Axons, Caenorhabditis elegans, Dendrites, Morphogenesis, Sensory Receptor Cells
Show Abstract · Added March 3, 2020
The shape of an individual neuron is linked to its function with axons sending signals to other cells and dendrites receiving them. Although much is known of the mechanisms for axonal outgrowth, the striking complexity of dendritic architecture has hindered efforts to uncover pathways that direct dendritic branching. Here we review the results of an experimental strategy that exploits the power of genetic analysis and live cell imaging of the PVD sensory neuron in C. elegans to reveal key molecular drivers of dendrite morphogenesis.
Copyright © 2019. Published by Elsevier Inc.
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MeSH Terms
NATF (Native and Tissue-Specific Fluorescence): A Strategy for Bright, Tissue-Specific GFP Labeling of Native Proteins in .
He S, Cuentas-Condori A, Miller DM
(2019) Genetics 212: 387-395
MeSH Terms: Animals, CRISPR-Cas Systems, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Fluorescence, Gene Editing, Green Fluorescent Proteins, Membrane Proteins, Nerve Tissue Proteins
Show Abstract · Added March 3, 2020
GFP labeling by genome editing can reveal the authentic location of a native protein, but is frequently hampered by weak GFP signals and broad expression across a range of tissues that may obscure cell-specific localization. To overcome these problems, we engineered a Native And Tissue-specific Fluorescence (NATF) strategy that combines genome editing and split-GFP to yield bright, cell-specific protein labeling. We use clustered regularly interspaced short palindromic repeats CRISPR/Cas9 to insert a tandem array of seven copies of the GFP11 β-strand ( ) at the genomic locus of each target protein. The resultant knock-in strain is then crossed with separate reporter lines that express the complementing split-GFP fragment () in specific cell types, thus affording tissue-specific labeling of the target protein at its native level. We show that NATF reveals the otherwise undetectable intracellular location of the immunoglobulin protein OIG-1 and demarcates the receptor auxiliary protein LEV-10 at cell-specific synaptic domains in the nervous system.
Copyright © 2019 by the Genetics Society of America.
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The CeNGEN Project: The Complete Gene Expression Map of an Entire Nervous System.
Hammarlund M, Hobert O, Miller DM, Sestan N
(2018) Neuron 99: 430-433
MeSH Terms: Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Chromosome Mapping, Gene Expression Profiling, National Institute of Neurological Disorders and Stroke (U.S.), Nervous System, Nervous System Physiological Phenomena, United States
Show Abstract · Added March 26, 2019
Differential gene expression defines individual neuron types and determines how each contributes to circuit physiology and responds to injury and disease. The C. elegans Neuronal Gene Expression Map & Network (CeNGEN) will establish a comprehensive gene expression atlas of an entire nervous system at single-neuron resolution.
Copyright © 2018. Published by Elsevier Inc.
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9 MeSH Terms
A Dendritic Guidance Receptor Complex Brings Together Distinct Actin Regulators to Drive Efficient F-Actin Assembly and Branching.
Zou W, Dong X, Broederdorf TR, Shen A, Kramer DA, Shi R, Liang X, Miller DM, Xiang YK, Yasuda R, Chen B, Shen K
(2018) Dev Cell 45: 362-375.e3
MeSH Terms: Actin Cytoskeleton, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cell Membrane, Dendrites, Membrane Proteins, Morphogenesis, Neurogenesis, Sensory Receptor Cells, Signal Transduction
Show Abstract · Added March 26, 2019
Proper morphogenesis of dendrites plays a fundamental role in the establishment of neural circuits. The molecular mechanism by which dendrites grow highly complex branches is not well understood. Here, using the Caenorhabditis elegans PVD neuron, we demonstrate that high-order dendritic branching requires actin polymerization driven by coordinated interactions between two membrane proteins, DMA-1 and HPO-30, with their cytoplasmic interactors, the RacGEF TIAM-1 and the actin nucleation promotion factor WAVE regulatory complex (WRC). The dendrite branching receptor DMA-1 directly binds to the PDZ domain of TIAM-1, while the claudin-like protein HPO-30 directly interacts with the WRC. On dendrites, DMA-1 and HPO-30 form a receptor-associated signaling complex to bring TIAM-1 and the WRC to close proximity, leading to elevated assembly of F-actin needed to drive high-order dendrite branching. The synergistic activation of F-actin assembly by scaffolding distinct actin regulators might represent a general mechanism in promoting complex dendrite arborization.
Copyright © 2018. Published by Elsevier Inc.
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MeSH Terms
Separate transcriptionally regulated pathways specify distinct classes of sister dendrites in a nociceptive neuron.
O'Brien BMJ, Palumbos SD, Novakovic M, Shang X, Sundararajan L, Miller DM
(2017) Dev Biol 432: 248-257
MeSH Terms: Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, DNA-Binding Proteins, Dendrites, Gene Expression Regulation, LIM-Homeodomain Proteins, Membrane Proteins, Nociceptors, Regulatory Elements, Transcriptional, Sensory Receptor Cells, Transcription Factors, Zinc Fingers
Show Abstract · Added March 26, 2019
The dendritic processes of nociceptive neurons transduce external signals into neurochemical cues that alert the organism to potentially damaging stimuli. The receptive field for each sensory neuron is defined by its dendritic arbor, but the mechanisms that shape dendritic architecture are incompletely understood. Using the model nociceptor, the PVD neuron in C. elegans, we determined that two types of PVD lateral branches project along the dorsal/ventral axis to generate the PVD dendritic arbor: (1) Pioneer dendrites that adhere to the epidermis, and (2) Commissural dendrites that fasciculate with circumferential motor neuron processes. Previous reports have shown that the LIM homeodomain transcription factor MEC-3 is required for all higher order PVD branching and that one of its targets, the claudin-like membrane protein HPO-30, preferentially promotes outgrowth of pioneer branches. Here, we show that another MEC-3 target, the conserved TFIIA-like zinc finger transcription factor EGL-46, adopts the alternative role of specifying commissural dendrites. The known EGL-46 binding partner, the TEAD transcription factor EGL-44, is also required for PVD commissural branch outgrowth. Double mutants of hpo-30 and egl-44 show strong enhancement of the lateral branching defect with decreased numbers of both pioneer and commissural dendrites. Thus, HPO-30/Claudin and EGL-46/EGL-44 function downstream of MEC-3 and in parallel acting pathways to direct outgrowth of two distinct classes of PVD dendritic branches.
Copyright © 2017 Elsevier Inc. All rights reserved.
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The Atypical MAP Kinase SWIP-13/ERK8 Regulates Dopamine Transporters through a Rho-Dependent Mechanism.
Bermingham DP, Hardaway JA, Refai O, Marks CR, Snider SL, Sturgeon SM, Spencer WC, Colbran RJ, Miller DM, Blakely RD
(2017) J Neurosci 37: 9288-9304
MeSH Terms: Animals, Animals, Genetically Modified, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cells, Cultured, Dopamine, Dopamine Plasma Membrane Transport Proteins, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Enzymologic, Neurons, rho-Associated Kinases
Show Abstract · Added March 21, 2018
The neurotransmitter dopamine (DA) regulates multiple behaviors across phylogeny, with disrupted DA signaling in humans associated with addiction, attention-deficit/ hyperactivity disorder, schizophrenia, and Parkinson's disease. The DA transporter (DAT) imposes spatial and temporal limits on DA action, and provides for presynaptic DA recycling to replenish neurotransmitter pools. Molecular mechanisms that regulate DAT expression, trafficking, and function, particularly , remain poorly understood, though recent studies have implicated rho-linked pathways in psychostimulant action. To identify genes that dictate the ability of DAT to sustain normal levels of DA clearance, we pursued a forward genetic screen in based on the phenotype swimming-induced paralysis (Swip), a paralytic behavior observed in hermaphrodite worms with loss-of-function mutations. Here, we report the identity of , which encodes a highly conserved ortholog of the human atypical MAP kinase ERK8. We present evidence that SWIP-13 acts presynaptically to insure adequate levels of surface DAT expression and DA clearance. Moreover, we provide and evidence supporting a conserved pathway involving SWIP-13/ERK8 activation of Rho GTPases that dictates DAT surface expression and function. Signaling by the neurotransmitter dopamine (DA) is tightly regulated by the DA transporter (DAT), insuring efficient DA clearance after release. Molecular networks that regulate DAT are poorly understood, particularly Using a forward genetic screen in the nematode , we implicate the atypical mitogen activated protein kinase, SWIP-13, in DAT regulation. Moreover, we provide and evidence that SWIP-13, as well as its human counterpart ERK8, regulate DAT surface availability via the activation of Rho proteins. Our findings implicate a novel pathway that regulates DA synaptic availability and that may contribute to risk for disorders linked to perturbed DA signaling. Targeting this pathway may be of value in the development of therapeutics in such disorders.
Copyright © 2017 the authors 0270-6474/17/379288-17$15.00/0.
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11 MeSH Terms
Neuroendocrine modulation sustains the forward motor state.
Lim MA, Chitturi J, Laskova V, Meng J, Findeis D, Wiekenberg A, Mulcahy B, Luo L, Li Y, Lu Y, Hung W, Qu Y, Ho CY, Holmyard D, Ji N, McWhirter R, Samuel AD, Miller DM, Schnabel R, Calarco JA, Zhen M
(2016) Elife 5:
MeSH Terms: Animals, Behavior, Animal, Caenorhabditis elegans, Locomotion, Neural Pathways, Neurons, Neuropeptides, Neurosecretory Systems, Neurotransmitter Agents
Show Abstract · Added March 26, 2019
Neuromodulators shape neural circuit dynamics. Combining electron microscopy, genetics, transcriptome profiling, calcium imaging, and optogenetics, we discovered a peptidergic neuron that modulates motor circuit dynamics. The Six/SO-family homeobox transcription factor UNC-39 governs lineage-specific neurogenesis to give rise to a neuron RID. RID bears the anatomic hallmarks of a specialized endocrine neuron: it harbors near-exclusive dense core vesicles that cluster periodically along the axon, and expresses multiple neuropeptides, including the FMRF-amide-related FLP-14. RID activity increases during forward movement. Ablating RID reduces the sustainability of forward movement, a phenotype partially recapitulated by removing FLP-14. Optogenetic depolarization of RID prolongs forward movement, an effect reduced in the absence of FLP-14. Together, these results establish the role of a neuroendocrine cell RID in sustaining a specific behavioral state in .
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