scholarly journals Cyclin-dependent-like kinase 5 is required for pain signalling in both human neurons and mouse models

2019 ◽  
Author(s):  
Paolo La Montanara ◽  
Arnau Hervera ◽  
Lucas Baltussen ◽  
Thomas Hutson ◽  
Ilaria Palmisano ◽  
...  
Keyword(s):  
Dorsal Root ◽  
Pain Perception ◽  
Regulatory Mechanism ◽  
Gene Mutations ◽  
Epileptic Encephalopathy ◽  
Murine Models ◽  
Drg Neurons ◽  
Conditional Deletion ◽  
Human Neurons ◽  
Deficient Mice

AbstractCyclin-dependent-like kinase 5 (Cdkl5) gene mutations lead to an X-linked disorder that is characterized by infantile epileptic encephalopathy, developmental delay and hypotonia. However, we found that a substantial percentage of these patients also report a previously unrecognised anamnestic deficiency in pain perception. Consistent with a role in nociception, we discovered that Cdkl5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in iPS-derived human nociceptors. CDKL5 deficient mice display defective epidermal innervation and conditional deletion of Cdkl5 in DRG sensory neurons significantly impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, Cdkl5 interacts with CaMKIIα to control outgrowth as well as TRPV1-dependent signalling, which are disrupted in both Cdkl5 mutant murine DRG and human iPS-derived nociceptors. Together, these findings unveil a previously unrecognized role for Cdkl5 in nociception, proposing an original regulatory mechanism for pain perception with implications for future therapeutics in CDKL5 deficiency disorder.One Sentence SummaryCyclin-dependent-like kinase 5 (Cdkl5) controls nociception in patients and murine models of Cdkl5 deficiency disorder via CaMKII-dependent mechanisms

scholarly journals Lrig1 and Lrig3 cooperate to control Ret receptor signaling, sensory axonal growth and epidermal innervation

Development ◽  
2021 ◽  
Author(s):  
Ana Paula De Vincenti ◽  
Fernando C. Alsina ◽  
Facundo Ferrero Restelli ◽  
Håkan Hedman ◽  
Fernanda Ledda ◽  
...  
Keyword(s):  
Physiological Response ◽  
Dorsal Root ◽  
Feedback Loop ◽  
Regulatory Mechanism ◽  
Axonal Growth ◽  
Drg Neurons ◽  
Single Deletion ◽  
Behavioral Sensitivity ◽  
And Function

Negative feedback-loop represents a regulatory mechanism that guarantees signaling thresholds compatible with a physiological response. Previously, we established that Lrig1, acts through this mechanism to inhibit Ret activity. However, it is unclear whether other Lrig-family members play similar roles. Here, we show that Lrig1 and Lrig3 are co-expressed in Ret-positive dorsal root ganglion (DRG) neurons. Lrig3, like Lrig1, interacts with Ret and inhibits GDNF/Ret signaling. Treatment of DRG neurons with GDNF ligands induces a significant increase in the expression of Lrig1 and Lrig3. Our findings show that whereas single deletion of either Lrig1 or Lrig3 fails to promote Ret-mediated axonal growth, haploinsufficiency of Lrig1 in Lrig3 mutants significantly potentiates Ret signaling and axonal growth of DRG neurons in response to GDNF ligands. We observe that Lrig1 and Lrig3 act redundantly to ensure proper cutaneous innervation of nonpeptidergic axons and behavioral sensitivity to cold, which correlate with a significant increase in the expression of the cold-responsive channel, TrpA1. Together our findings provide novel insights into the in vivo functions through which Lrig genes control morphology, connectivity and function in sensory neurons.

scholarly journals Cyclin-dependent–like kinase 5 is required for pain signaling in human sensory neurons and mouse models

2020 ◽  
Vol 12 (551) ◽  
pp. eaax4846 ◽  
Author(s):  
Paolo La Montanara ◽  
Arnau Hervera ◽  
Lucas L. Baltussen ◽  
Thomas H. Hutson ◽  
Ilaria Palmisano ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Pain Perception ◽  
Transient Receptor Potential ◽  
Gene Mutations ◽  
Induced Pluripotent Stem Cell ◽  
Receptor Potential ◽  
Epileptic Encephalopathy ◽  
Calcium Calmodulin Dependent ◽  
Transient Receptor ◽  
Induced Pluripotent

Cyclin-dependent–like kinase 5 (CDKL5) gene mutations lead to an X-linked disorder that is characterized by infantile epileptic encephalopathy, developmental delay, and hypotonia. However, we found that a substantial percentage of these patients also report a previously unrecognized anamnestic deficiency in pain perception. Consistent with a role in nociception, we found that CDKL5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in induced pluripotent stem cell (iPS)–derived human nociceptors. CDKL5-deficient mice display defective epidermal innervation, and conditional deletion of CDKL5 in DRG sensory neurons impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, CDKL5 interacts with calcium/calmodulin-dependent protein kinase II α (CaMKIIα) to control outgrowth and transient receptor potential cation channel subfamily V member 1 (TRPV1)–dependent signaling, which are disrupted in both CDKL5 mutant murine DRG and human iPS–derived nociceptors. Together, these findings unveil a previously unrecognized role for CDKL5 in nociception, proposing an original regulatory mechanism for pain perception with implications for future therapeutics in CDKL5 deficiency disorder.

scholarly journals hNGF Peptides Elicit the NGF-TrkA Signalling Pathway in Cholinergic Neurons and Retain Full Neurotrophic Activity in the DRG Assay

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 216 ◽  
Author(s):  
Viviana Triaca ◽  
Elena Fico ◽  
Valentina Sposato ◽  
Silvia Caioli ◽  
Maria Teresa Ciotti ◽  
...  
Keyword(s):  
Dorsal Root ◽  
Cholinergic Neurons ◽  
Early Gene ◽  
Low Molecular Weight ◽  
Primary Neurons ◽  
Brain Delivery ◽  
Drg Neurons ◽  
Neurotrophic Activity ◽  
Mapk Signalling

In the last decade, Nerve Growth Factor (NGF)-based clinical approaches have lacked specific and efficient Tyrosine Kinase A (TrkA) agonists for brain delivery. Nowadays, the characterization of novel small peptidomimetic is taking centre stage in preclinical studies, in order to overcome the main size-related limitation in brain delivery of NGF holoprotein for Central Nervous System (CNS) pathologies. Here we investigated the NGF mimetic properties of the human NGF 1–14 sequence (hNGF1–14) and its derivatives, by resorting to primary cholinergic and dorsal root ganglia (DRG) neurons. Briefly, we observed that: 1) hNGF1–14 peptides engage the NGF pathway through TrkA phosphorylation at tyrosine 490 (Y490), and activation of ShcC/PI3K and Plc-γ/MAPK signalling, promoting AKT-dependent survival and CREB-driven neuronal activity, as seen by levels of the immediate early gene c-Fos, of the cholinergic marker Choline Acetyltransferase (ChAT), and of Brain Derived Neurotrophic Factor (BDNF); 2) their NGF mimetic activity is lost upon selective TrkA inhibition by means of GW441756; 3) hNGF1–14 peptides are able to sustain DRG survival and differentiation in absence of NGF. Furthermore, the acetylated derivative Ac-hNGF1–14 demonstrated an optimal NGF mimetic activity in both neuronal paradigms and an electrophysiological profile similar to NGF in cholinergic neurons. Cumulatively, the findings here reported pinpoint the hNGF1–14 peptide, and in particular its acetylated derivative, as novel, specific and low molecular weight TrkA specific agonists in both CNS and PNS primary neurons.

scholarly journals Expression of Cholinergic Markers and Characterization of Splice Variants during Ontogenesis of Rat Dorsal Root Ganglia Neurons

2021 ◽  
Vol 22 (11) ◽  
pp. 5499
Author(s):  
Veronica Corsetti ◽  
Carla Perrone-Capano ◽  
Michael Sebastian Salazar Intriago ◽  
Elisabetta Botticelli ◽  
Giancarlo Poiana ◽  
...  
Keyword(s):  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Splice Variants ◽  
Multiple Roles ◽  
Pcr Analysis ◽  
Drg Neurons ◽  
Embryonic Developmental Stage ◽  
Embryo Stage ◽  
Dorsal Root Ganglia Neurons ◽  
Cholinergic Markers

Dorsal root ganglia (DRG) neurons synthesize acetylcholine (ACh), in addition to their peptidergic nature. They also release ACh and are cholinoceptive, as they express cholinergic receptors. During gangliogenesis, ACh plays an important role in neuronal differentiation, modulating neuritic outgrowth and neurospecific gene expression. Starting from these data, we studied the expression of choline acetyltransferase (ChAT) and vesicular ACh transporter (VAChT) expression in rat DRG neurons. ChAT and VAChT genes are arranged in a “cholinergic locus”, and several splice variants have been described. Using selective primers, we characterized splice variants of these cholinergic markers, demonstrating that rat DRGs express R1, R2, M, and N variants for ChAT and V1, V2, R1, and R2 splice variants for VAChT. Moreover, by RT-PCR analysis, we observed a progressive decrease in ChAT and VAChT transcripts from the late embryonic developmental stage (E18) to postnatal P2 and P15 and in the adult DRG. Interestingly, Western blot analyses and activity assays demonstrated that ChAT levels significantly increased during DRG ontogenesis. The modulated expression of different ChAT and VAChT splice variants during development suggests a possible differential regulation of cholinergic marker expression in sensory neurons and confirms multiple roles for ACh in DRG neurons, both in the embryo stage and postnatally.

scholarly journals Regulatory mechanism of gastric acid secretion and mucosal integrity. An analysis with various gene deficient mice.

2002 ◽  
Vol 120 (3) ◽  
pp. 159-171 ◽  
Author(s):  
Susumu OKABE ◽  
Kazuharu FURUTANI ◽  
Kazuhiko MAEDA ◽  
Takeshi AIHARA ◽  
Teruaki FUJISHITA ◽  
...  
Keyword(s):  
Acid Secretion ◽  
Gastric Acid Secretion ◽  
Gastric Acid ◽  
Regulatory Mechanism ◽  
Mucosal Integrity ◽  
Deficient Mice

scholarly journals Hamster and Murine Models of Severe Destructive Lyme Arthritis

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Erik Munson ◽  
Dean T. Nardelli ◽  
Brian K. Du Chateau ◽  
Steven M. Callister ◽  
Ronald F. Schell
Keyword(s):  
Lyme Borreliosis ◽  
Bone Erosion ◽  
Lyme Arthritis ◽  
Murine Models ◽  
Transient Synovitis ◽  
Hamster Model ◽  
C3h Mice ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Reaction Characteristic

Arthritis is a frequent complication of infection in humans withBorrelia burgdorferi. Weeks to months following the onset of Lyme borreliosis, a histopathological reaction characteristic of synovitis including bone, joint, muscle, or tendon pain may occur. A subpopulation of patients may progress to a chronic, debilitating arthritis months to years after infection which has been classified as severe destructive Lyme arthritis. This arthritis involves focal bone erosion and destruction of articular cartilage. Hamsters and mice are animal models that have been utilized to study articular manifestations of Lyme borreliosis. Infection of immunocompetent LSH hamsters or C3H mice results in a transient synovitis. However, severe destructive Lyme arthritis can be induced by infecting irradiated hamsters or mice and immunocompetentBorrelia-vaccinated hamsters, mice, and interferon-gamma- (IFN-γ-) deficient mice with viableB. burgdorferi. The hamster model of severe destructive Lyme arthritis facilitates easy assessment of Lyme borreliosis vaccine preparations for deleterious effects while murine models of severe destructive Lyme arthritis allow for investigation of mechanisms of immunopathology.

scholarly journals Effects of DSPP Gene Mutations on Periodontal Tissues

2021 ◽  
Author(s):  
Zhaojun Jing ◽  
Zhibin Chen ◽  
Yong Jiang
Keyword(s):  
Alveolar Bone ◽  
Gene Mutations ◽  
Specific Protein ◽  
Dentinogenesis Imperfecta ◽  
Dentin Sialophosphoprotein ◽  
Periodontal Tissues ◽  
Furcation Involvement ◽  
Almost All ◽  
Alveolar Bone Defect ◽  
Deficient Mice

AbstractDentin sialophosphoprotein (DSPP) gene mutations cause autosomal dominantly inherited diseases. DSPP gene mutations lead to abnormal expression of DSPP, resulting in a series of histological, morphological, and clinical abnormalities. A large number of previous studies demonstrated that DSPP is a dentinal-specific protein, and DSPP gene mutations lead to dentin dysplasia and dentinogenesis imperfecta. Recent studies have found that DSPP is also expressed in bone, periodontal tissues, and salivary glands. DSPP is involved in the formation of the periodontium as well as tooth structures. DSPP deficient mice present furcation involvement, cementum, and alveolar bone defect. We speculate that similar periodontal damage may occur in patients with DSPP mutations. This article reviews the effects of DSPP gene mutations on periodontal status. However, almost all of the research is about animal study, there is no evidence that DSPP mutations cause periodontium defects in patients yet. We need to conduct systematic clinical studies on DSPP mutation families in the future to elucidate the effect of DSPP gene on human periodontium.

Dorsal Root Ganglion Neuron Types and Their Functional Specialization

2018 ◽  
pp. 127-155 ◽  
Author(s):  
Edward C. Emery ◽  
Patrik Ernfors
Keyword(s):  
Chronic Pain ◽  
Dorsal Root Ganglion ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Drg Neurons ◽  
Low Threshold

Primary sensory neurons of the dorsal root ganglion (DRG) respond and relay sensations that are felt, such as those for touch, pain, temperature, itch, and more. The ability to discriminate between the various types of stimuli is reflected by the existence of specialized DRG neurons tuned to respond to specific stimuli. Because of this, a comprehensive classification of DRG neurons is critical for determining exactly how somatosensation works and for providing insights into cell types involved during chronic pain. This article reviews the recent advances in unbiased classification of molecular types of DRG neurons in the perspective of known functions as well as predicted functions based on gene expression profiles. The data show that sensory neurons are organized in a basal structure of three cold-sensitive neuron types, five mechano-heat sensitive nociceptor types, four A-Low threshold mechanoreceptor types, five itch-mechano-heat–sensitive nociceptor types and a single C–low-threshold mechanoreceptor type with a strong relation between molecular neuron types and functional types. As a general feature, each neuron type displays a unique and predicable response profile; at the same time, most neuron types convey multiple modalities and intensities. Therefore, sensation is likely determined by the summation of ensembles of active primary afferent types. The new classification scheme will be instructive in determining the exact cellular and molecular mechanisms underlying somatosensation, facilitating the development of rational strategies to identify causes for chronic pain.

scholarly journals ATP metabolizing enzymes ENPP1, 2 and 3 are localized in sensory neurons of rat dorsal root ganglion

2018 ◽  
Author(s):  
Kentaro Nishida ◽  
Yuka Nomura ◽  
Kanako Kawamori ◽  
Akihiro Ohishi ◽  
Kazuki Nagasawa
Keyword(s):  
Dorsal Root Ganglion ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Adenine Nucleotide ◽  
Expression Profiles ◽  
Critical Role ◽  
Immunohistochemical Analysis ◽  
Uptake System ◽  
Nucleoside Transporter ◽  
Drg Neurons

In dorsal root ganglion (DRG) neurons, ATP is an important neurotransmitter in nociceptive signaling through P2 receptors (P2Rs) such as P2X2/3R, and adenosine is also involved in anti-nociceptive signaling through adenosine A1R. Thus, the clearance system for adenine nucleotide/nucleoside plays a critical role in regulation of nociceptive signaling, but there is little information on it, especially ectoenzyme expression profiles in DRG. In this study, we examined expression and localization of ecto-nucleotide pyrophosphatase/phosphodiesterases (ENPPs), by which ATP is metabolized to AMP, in rat DRG. The mRNA expression levels of ENPP2 were greater than those of ENPP1 and ENPP3 in rat DRGs. On immunohistochemical analysis, ENPP1, 2 and 3 were found in soma of DRG neurons. Immunopositive rate of ENPP3 was greater than that of ENPP1 and ENPP2 in all DRG neurons. ENPP3, as compared with ENPP1 and ENPP2, was expressed mainly by isolectin B4-positive cells, and slightly by neurofilament 200-positive ones. In this way, the expression profile of ENPP1, 2 and 3 was different in DRGs, and they were mainly expressed in small/medium-sized DRG neurons. Moreover, ENPP1-, 2- and 3-immunoreactivities were colocalized with P2X2R, P2X3R and prostatic acid phosphatase (PAP), as an ectoenzyme for metabolism from AMP to adenosine. Additionally, PAP-immunoreactivity was colocalized with equilibrative nucleoside transporter (ENT) 1, as an adenosine uptake system. These results suggest that the clearance system consisted of ENPPs, PAP and ENT1 plays an important role in regulation of nociceptive signaling in sensory neurons.

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