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| Open AccessSensory Schwann cells set perceptual thresholds for touch and selectively regulate mechanical nociception
Schwann cells associated with most sensory receptors in the skin actively participate in the transduction of mechanical stimuli. Here the authors show that silencing these sensory Schwann cells is sufficient to reduce touch perception and can inhibit mechanical pain in mice.
- Julia Ojeda-Alonso
- , Laura Calvo-Enrique
- & Gary R. Lewin
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Article
| Open AccessSoft ferroelectret ultrasound receiver for targeted peripheral neuromodulation
Neurostimulators are often bulky and uncomfortable. Researchers report a wireless, leadless, and battery-free ultrasound receiver that wraps around the target peripheral nerve and allows precise modulation of organ function, providing a framework for future bioelectronic medicines
- Tong Li
- , Zhidong Wei
- & Zhang-Qi Feng
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Article
| Open AccessFully implanted battery-free high power platform for chronic spinal and muscular functional electrical stimulation
Electrical stimulation of the neuromuscular system holds promise for therapeutic biomedical applications, but is currently restricted by power. Here, the authors introduce fully implantable resonator-based designs achieving ±20 V compliance and >300 mW output, enabling multichannel, biphasic, current-controlled operation to evoke functional gate patterns for 6-weeks in freely behaving rats.
- Alex Burton
- , Zhong Wang
- & Philipp Gutruf
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Article
| Open AccessVagus nerve stimulation primes platelets and reduces bleeding in hemophilia A male mice
Coagulation factor VIII deficiency in hemophilia A disrupts clotting and prolongs bleeding. Here, the authors show that vagus nerve stimulation bypasses this defect and improves hemostasis in hemophilia A mice through a mechanism requiring acetylcholine-secreting ChAT+ T lymphocytes in spleen and α7nAChR on circulating platelets.
- Carlos E. Bravo-Iñiguez
- , Jason R. Fritz
- & Jared M. Huston
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Article
| Open AccessPiezo2 expressing nociceptors mediate mechanical sensitization in experimental osteoarthritis
Osteoarthritis is characterized by mechanically driven pain but lacks adequate treatments. Here, the authors show that inhibiting a mechanically-sensitive ion channel expressed by nociceptors reduces pain behaviors in mouse models of joint pain.
- Alia M. Obeidat
- , Matthew J. Wood
- & Rachel E. Miller
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| Open AccessRole of TMEM100 in mechanically insensitive nociceptor un-silencing
Silent nociceptors remained enigmatic ever since they were first described decades ago. Here, Nees. et al. show that inflammation-induced upregulation of TMEM100 unsilences silent nociceptors, which triggers secondary mechanical pain hypersensitivity.
- Timo A. Nees
- , Na Wang
- & Stefan G. Lechner
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Article
| Open AccessIntrafusal-fiber LRP4 for muscle spindle formation and maintenance in adult and aged animals
Muscle spindles sense muscle tension to coordinate body movement. This paper reveals a mechanism of spindle formation and maintenance and to better understanding changes in movement in muscle disorders and ageing.
- Rangjuan Cao
- , Peng Chen
- & Lin Mei
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Article
| Open AccessSynchronized activity of sensory neurons initiates cortical synchrony in a model of neuropathic pain
Increased low frequency cortical oscillations are observed in neuropathic pain. Here the authors perform Ca2+ imaging of DRG sensory neurons in a mouse model of neuropathic pain, and show that synchronized activity of DRG neurons occurs within hours after injury and 1-2 days before increased cortical oscillations are observed.
- Chao Chen
- , Linlin Sun
- & Peifu Tang
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Article
| Open AccessNorepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models
Sympathetic neurons are affected in familial dysautonomia, a rare disease associated with a mutation in ELP1, but the mechanisms are not fully understood. Here the authors show, using neurons derived from participants with familial dysauotnomia, that spontaneous sympathetic neuron hyperactivity is observed and is associated with norepinephrine transporter deficits.
- Hsueh-Fu Wu
- , Wenxin Yu
- & Nadja Zeltner
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Article
| Open AccessSympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer
The autonomic nervous systems densely innervate the pancreas, but its contribution to pancreatic ductal adenocarcinoma (PDAC) progression is not fully understood. Here, the authors characterize the pattern of sympathetic innervation by 3D imaging in a murine model of PDAC and show that sympathectomy aggravates cancer progression.
- Jérémy Guillot
- , Chloé Dominici
- & Fanny Mann
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Article
| Open AccessNGF-TrkA signaling dictates neural ingrowth and aberrant osteochondral differentiation after soft tissue trauma
Soft tissue trauma can result in aberrant osteochondral differentiation of local mesenchymal progenitor cells. Here the authors show that, in mice, soft tissue trauma results in NGF expression by perivascular cells, which leads to axonal invasion and drives abnormal osteochondral differentiation, and show that this process can be prevented by inhibition of NGF signaling.
- Seungyong Lee
- , Charles Hwang
- & Benjamin Levi
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Article
| Open AccessMolecular and cellular basis of acid taste sensation in Drosophila
Many animals, including mammals and insects, like slightly acidic yet dislike highly acidic foods, but how animals discriminate low from high acidity is unclear. Here the authors demonstrate that the fruit fly uses an evolutionarily conserved taste receptor to distinguish low from high concentrations of acid.
- Tingwei Mi
- , John O. Mack
- & Yali V. Zhang
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Article
| Open AccessAAV2/9-mediated silencing of PMP22 prevents the development of pathological features in a rat model of Charcot-Marie-Tooth disease 1 A
Charcot-Marie-Tooth disease 1 A (CMT1A) results from PMP22 gene duplication and is characterized by peripheral nerve myelination deficits. Here, the authors prevent the development of pathological features in a rat model of CMT1A through the local delivery of AAV2/9 expressing shRNAs against PMP22.
- Benoit Gautier
- , Helene Hajjar
- & Nicolas Tricaud
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Article
| Open AccessSingle cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain
The contribution of distinct types of dorsal root ganglion neurons to chronic pain is unclear. Here, the authors molecularly profile non-human primate sensory neurons and show that genome-wide associations converge on two neuronal types with different genetic susceptibilities for chronic pain.
- Jussi Kupari
- , Dmitry Usoskin
- & Patrik Ernfors
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Article
| Open AccessMolecular correlates of muscle spindle and Golgi tendon organ afferents
Coordinated movement critically depends on sensory feedback from muscle spindles (MSs) and Golgi tendon organs (GTOs) but the afferents supplying this proprioceptive feedback have remained genetically inseparable. Here the authors use single cell transcriptome analysis to reveal the molecular basis of MS (groups Ia and II) and GTO (group Ib) afferent identities in the mouse.
- Katherine M. Oliver
- , Danny M. Florez-Paz
- & Joriene C. de Nooij
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Article
| Open AccessInnocuous pressure sensation requires A-type afferents but not functional ΡΙΕΖΟ2 channels in humans
The mechanisms underlying deep pressure sensing are not fully understood. Here the authors demonstrate that while two individuals lacking Aβ fibers demonstrate impaired deep pressure sensing, seven individuals with PIEZO2 loss of function mutations display normal deep pressure responses.
- Laura K. Case
- , Jaquette Liljencrantz
- & Alexander T. Chesler
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Article
| Open AccessOrgan-specific, multimodal, wireless optoelectronics for high-throughput phenotyping of peripheral neural pathways
Advances in wireless technologies have enabled internalisation of light sources, but organ specific illumination is challenging. Here, the authors present a durable, multimodal, wireless system enabling optogenetic stimulation of peripheral neurons within organs.
- Woo Seok Kim
- , Sungcheol Hong
- & Sung Il Park
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Article
| Open AccessOptogenetic stimulation of the liver-projecting melanocortinergic pathway promotes hepatic glucose production
Hypothalamic melanocortin neurons regulate systemic glucose homeostasis through incompletely understood pathways. Here, the authors show that a subset of pro-opiomelanocortin neurons innervate the liver via preganglionic parasympathetic cholinergic neurons in the dorsal motor nucleus of the vagus and that stimulation of this pathway elevates blood glucose levels
- Eunjin Kwon
- , Hye-Young Joung
- & Young-Hwan Jo
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Article
| Open AccessImaging fascicular organization of rat sciatic nerves with fast neural electrical impedance tomography
To be successful, selective neuromodulation requires a non-invasive method of imaging the fascicular anatomy of peripheral nerves. Here, the authors show the applicability and reliability of fast neural electrical impedance tomography for this purpose and provide its validation against the gold standards of invasive imaging.
- Enrico Ravagli
- , Svetlana Mastitskaya
- & David Holder
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Article
| Open AccessMEKK2 mediates aberrant ERK activation in neurofibromatosis type I
Neurofibromatosis type I (NF1) is characterized by prominent skeletal abnormalities mediated in part by aberrant ERK pathway activation due to NF1 loss-of-function. Here, the authors report the MEKK2 is a key mediator of this aberrant ERK activation and that MEKK2 inhibitors, including ponatinib, ameliorate skeletal defects in a mouse model of NF1.
- Seoyeon Bok
- , Dong Yeon Shin
- & Matthew B. Greenblatt
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Article
| Open AccesscAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells
The involvement of cAMP-dependent regulation of HCN4 in the chronotropic heart rate response is a matter of debate. Here the authors use a knockin mouse model expressing cAMP-insensitive HCN4 channels to discover an inhibitory nonfiring cell pool in the sinoatrial node and a tonic and mutual interaction between firing and nonfiring pacemaker cells that is controlled by cAMP-dependent regulation of HCN4, with implications in chronotropic heart rate responses.
- Stefanie Fenske
- , Konstantin Hennis
- & Christian Wahl-Schott
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Article
| Open AccessSatellite glial cells promote regenerative growth in sensory neurons
The contribution of satellite glia to peripheral nerve regeneration is unclear. Here, the authors show that satellite glia are transcriptionally distinct from Schwann cells, share similarities with astrocytes, and, upon injury, they contribute to axon regeneration via Fasn-PPARα signalling pathway.
- Oshri Avraham
- , Pan-Yue Deng
- & Valeria Cavalli
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Article
| Open AccessCMTM6 expressed on the adaxonal Schwann cell surface restricts axonal diameters in peripheral nerves
Myelinating cells differentially myelinate axons of different diameters, however whether they can also restrict radial axonal growth remained unclear. Here, the authors show that CMTM6 in Schwann cells restricts axon diameters, affecting sensory nerve conduction and behavioral performance.
- Maria A. Eichel
- , Vasiliki-Ilya Gargareta
- & Hauke B. Werner
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Article
| Open AccessPrintable microscale interfaces for long-term peripheral nerve mapping and precision control
Modulation of peripheral nervous system signalling has many applications in medicine, neurobiology and machine-man interfaces. Here the authors develop a microscale implantable device for chronic interfacing with a small diameter nerve, and show multi-week in vivo recording and control of activity.
- Timothy M. Otchy
- , Christos Michas
- & Timothy J. Gardner
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Article
| Open AccessTRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca2+
Mutations in the TRPV4 channel cause inherited neurodegeneration syndromes, but the molecular mechanisms are unknown. Here the authors reveal that TRPV4 activation causes dose-dependent, CaMKII-mediated neuronal dysfunction and axonal degeneration via disruption of mitochondrial axonal transport.
- Brian M. Woolums
- , Brett A. McCray
- & Thomas E. Lloyd
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Article
| Open AccessSpider venom-derived peptide induces hyperalgesia in Nav1.7 knockout mice by activating Nav1.9 channels
Loss of function of Nav1.7 leads to congenital insensitivity to pain in humans. Here the authors found that activation of Nav1.9 can restore nociception in Nav1.7 knockout mice, revealed by a venom-derived peptide as a probe.
- Xi Zhou
- , Tingbin Ma
- & Zhonghua Liu
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Article
| Open AccessLipid metabolism adaptations are reduced in human compared to murine Schwann cells following injury
The regeneration dynamics following peripheral nerve injury differs among species. Here, the authors compared transcriptomic and lipid metabolism changes in murine and human Schwann cells in vivo and ex vivo sural nerves, underlying their switch from myelinating to repair state following injury.
- Sofia Meyer zu Reckendorf
- , Christine Brand
- & Bernd Knöll
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Article
| Open AccessActive acetylcholine receptors prevent the atrophy of skeletal muscles and favor reinnervation
Denervation of muscle fibres induces muscle atrophy, via mechanisms that remain unclear. Here, the authors show that binding of acetylcoline to its receptor at the neuromuscular junction represses the expression of connexins 43 and 45, which promote atrophy, and is sufficient to prevent denervation-induced loss of myofibre mass.
- Bruno A. Cisterna
- , Aníbal A. Vargas
- & Juan C. Sáez
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Article
| Open AccessAutonomic ganglionic injection of α-synuclein fibrils as a model of pure autonomic failure α-synucleinopathy
Autonomic dysfunction is a feature of some α-synucleinopathies, but there are no models of pure autonomic dysfunction associated with α-synuclein. Here the authors describe a mouse model of pure autonomic dysfunction without motor dysfunciton by injection of pre-formed fibrils of α-synuclein to the stellate and celiac ganglia.
- Xue-Jing Wang
- , Ming-Ming Ma
- & Xue-Bing Ding
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Article
| Open AccessStructural basis for adhesion G protein-coupled receptor Gpr126 function
The extracellular regions (ECRs) of adhesion GPCRs have diverse biological functions, but their structures and mechanisms of action remain unclear. Here, the authors solve the ECR structure of the Gpr126 receptor and show that ECR conformation and signaling functions are regulated by alternative splicing.
- Katherine Leon
- , Rebecca L. Cunningham
- & Demet Araç
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Article
| Open AccessEnhancing plasticity in central networks improves motor and sensory recovery after nerve damage
Peripheral nerve damage generates maladaptive neuroplasticity as central networks attempt to compensate for the loss of peripheral connectivity. Here, the authors reverse the aberrant plasticity via vagus nerve stimulation to elicit synaptic reorganization and to improve sensorimotor recovery.
- Eric C. Meyers
- , Nimit Kasliwal
- & Seth A. Hays
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Article
| Open AccessPupil-linked phasic arousal evoked by violation but not emergence of regularity within rapid sound sequences
The neurotransmitter Norepinephrine (NE) has been implicated in coding surprise during decision making. Here, the authors demonstrate that this extends to sensory processing: NE release is specific to unexpected events even on extremely rapid time scales and without explicit tracking of probability.
- Sijia Zhao
- , Maria Chait
- & Hsin-I Liao
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Article
| Open AccessmTORC1 and PKB/Akt control the muscle response to denervation by regulating autophagy and HDAC4
Denervation leads to muscle atrophy and neuromuscular endplate remodeling. Here, the authors show that a balanced activation of mTORC1 contributes to the dynamic regulation of autophagic flux in denervated muscle and that activation of PKB/Akt promotes the nuclear import of HDAC4, which is essential for endplate maintenance upon nerve injury
- Perrine Castets
- , Nathalie Rion
- & Markus A. Rüegg
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Article
| Open AccessLong-term imaging of dorsal root ganglia in awake behaving mice
Imaging sensory neurons in the dorsal root ganglion (DRG) in awake animals is challenging due to motion artefacts and other technical issues. Here the authors develop an intervertebral fusion procedure which minimizes spinal movement thereby enabling chronic imaging of DRG neurons in awake, behaving mice.
- Chao Chen
- , Jinhui Zhang
- & Guang Yang
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Article
| Open AccessIdentification of peripheral neural circuits that regulate heart rate using optogenetic and viral vector strategies
The wiring of peripheral neural circuits that regulate heart rate is poorly understood. In this study, authors used tissue clearing for high-resolution characterization of nerves in the heart in 3D and transgenic and novel viral vector approaches to identify peripheral parasympathetic and sympathetic neuronal populations involved in heart rate control in mice.
- Pradeep S. Rajendran
- , Rosemary C. Challis
- & Kalyanam Shivkumar
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Article
| Open AccessA PRPH splice-donor variant associates with reduced sural nerve amplitude and risk of peripheral neuropathy
Diagnosis and classification of peripheral neuropathy (PN) is facilitated by nerve conduction (NC) studies. Here, Bjornsdottir et al. find a low-frequency PRPH splice-donor variant that associates with NC amplitude and neurological assessment of recalled PRPH variant carriers reveals increased risk of a mild sensory-negative PN.
- Gyda Bjornsdottir
- , Erna V. Ivarsdottir
- & Kari Stefansson
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Article
| Open AccessNoninvasive sub-organ ultrasound stimulation for targeted neuromodulation
Stimulation of peripheral nerve activity may be used to treat metabolic and inflammatory disorders, but current approaches need implanted devices. Here, the authors present a non-invasive approach, and show that ultrasound-mediated stimulation can be targeted to specific sub-organ locations in preclinical models and alter the response of metabolic and inflammatory neural pathways.
- Victoria Cotero
- , Ying Fan
- & Christopher Puleo
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Article
| Open AccesstACS motor system effects can be caused by transcutaneous stimulation of peripheral nerves
Transcranial alternating current stimulation (tACS) uses weak electrical currents, applied to the head, to modulate brain activity. Here, the authors show that contrary to previous assumptions, the effects of tACS on the brain may be mediated by its effect on peripheral nerves in the skin, not direct.
- Boateng Asamoah
- , Ahmad Khatoun
- & Myles Mc Laughlin
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Article
| Open AccessThe synaptic receptor Lrp4 promotes peripheral nerve regeneration
Axons of the peripheral nervous system regenerate along Schwann cells following injury. Here, the authors show that regenerating axons follow pioneer axons and this process is mediated by lipoprotein receptor-related protein 4 (Lrp4), a protein otherwise known for its role in synapse formation.
- Katherine D. Gribble
- , Lauren J. Walker
- & Michael Granato
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Article
| Open AccessSemaphorin 4C Plexin-B2 signaling in peripheral sensory neurons is pronociceptive in a model of inflammatory pain
Semaphorins and their receptors are involved in neurodevelopment, but their functions in the adult nervous system are not fully understood. This study finds that semaphorin 4C and its receptor Plexin B are expressed in sensory neurons and are pronociceptive in a mouse model of inflammatory pain.
- Eszter Paldy
- , Manuela Simonetti
- & Rohini Kuner
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Article
| Open AccessRegulation of Drosophila hematopoietic sites by Activin-β from active sensory neurons
Hematopoietic sites in theDrosophilalarva require the local peripheral nervous system for blood cells (hemocytes) to survive and proliferate, but how this is mediated is unclear. Here, the authors identify Activin-β from sensory neurons as signalling to hemocytes, affecting proliferation and adhesion.
- Kalpana Makhijani
- , Brandy Alexander
- & Katja Brückner
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Article
| Open AccessVagal determinants of exercise capacity
Demonstrating a causal relationship between cardiac vagal tone and exercise capacity has been previously limited by methodological constraints. Using genetic targeting, silencing and optogenetic recruitment of vagal motor neuron activity in rodents, Machhadaet al. provide direct evidence that vagal drive determines the ability to exercise.
- Asif Machhada
- , Stefan Trapp
- & Alexander V. Gourine
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Article
| Open AccessA brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages
Diphtheria toxin selectively kills cells engineered to express the diphtheria toxin receptor (DTR). Here the authors report a PEGylated version of diphtheria toxin that does not enter the brain, allowing for ablation of only peripheral cells when using Cre lines that drive DTR expression in both the periphery and in the brain.
- Mafalda M. A. Pereira
- , Inês Mahú
- & Ana I. Domingos
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Article
| Open AccessMicroglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury
Microglia and monocytes contribute to neuropathic pain states, but the precise role of the two cell types is not clear. Here Peng et al.use temporally controlled ablation of monocytes and microglia in mice to show that these cells work together to initiate neuropathic-pain like behaviour, but are less important in the maintenance phase.
- Jiyun Peng
- , Nan Gu
- & Long-Jun Wu
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Article
| Open AccessSimultaneous optical and electrical in vivo analysis of the enteric nervous system
The enteric nervous system (ENS) plays a key role in regulating gut motility and homeostasis yet it remains a challenging system to record from. Here, the authors develop a novel abdominal window permitting simultaneous optical and electrical recording of mouse ENS system activity over prolonged time periods.
- Nikolai Rakhilin
- , Bradley Barth
- & Xiling Shen
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Article
| Open AccessGenetic pathways for differentiation of the peripheral nervous system in ascidians
The evolutionary origin of the peripheral nervous systems (PNSs) is poorly understood. Here, the authors show that two mechanisms activate gene circuits in ascidians to differentiate epidermal sensory neurons, which suggests that vertebrate PNSs arose via cooption of the ancient PNS gene circuit.
- Kana Waki
- , Kaoru S. Imai
- & Yutaka Satou
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Article
| Open AccessThe Lin28/let-7 axis is critical for myelination in the peripheral nervous system
MicroRNAs are known to regulate myelination in the peripheral nervous system, but the underlying mechanisms remain unclear. Here the authors show that the Lin28B/let-7 axis drives the onset of myelination by promoting Krox20 expression through suppression of Notch signalling.
- Deniz Gökbuget
- , Jorge A. Pereira
- & Ueli Suter
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The origin of segmentation motor activity in the intestine
The segmentation motor activity of the small intestine is believed to be a result of alternating inhibitory and excitatory neural activity. Huizinga et al.show that the segmentation motor pattern is in fact a result of phase–amplitude interactions of slow-wave activities generated by two networks of interstitial cells of Cajal.
- Jan D. Huizinga
- , Ji-Hong Chen
- & David Chen
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Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity
Interstitial cells of Cajal generate rhythmic pacemaker currents, which result in rhythmic bowel contractions. Klein and colleagues use knock-in mutations to inactivate these cells in mice and find that they modulate bowel contractions by integrating excitatory and inhibitory neurotransmission in the gut.
- Sabine Klein
- , Barbara Seidler
- & Dieter Saur