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Developmentally regulated KCC2 phosphorylation is essential for dynamic GABA-mediated inhibition and survival.
Watanabe M, Zhang J, Mansuri MS, Duan J, Karimy JK, Delpire E, Alper SL, Lifton RP, Fukuda A, Kahle KT
(2019) Sci Signal 12:
MeSH Terms: Animals, Animals, Newborn, Binding Sites, Cells, Cultured, Central Nervous System, Chlorides, Gene Expression Regulation, Developmental, Male, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Neurons, Phosphorylation, Signal Transduction, Symporters, gamma-Aminobutyric Acid
Show Abstract · Added March 18, 2020
Despite its importance for γ-aminobutyric acid (GABA) inhibition and involvement in neurodevelopmental disease, the regulatory mechanisms of the K/Cl cotransporter KCC2 (encoded by ) during maturation of the central nervous system (CNS) are not entirely understood. Here, we applied quantitative phosphoproteomics to systematically map sites of KCC2 phosphorylation during CNS development in the mouse. KCC2 phosphorylation at Thr and Thr, which inhibits KCC2 activity, underwent dephosphorylation in parallel with the GABA excitatory-inhibitory sequence in vivo. Knockin mice expressing the homozygous phosphomimetic KCC2 mutations T906E/T1007E ( ), which prevented the normal developmentally regulated dephosphorylation of these sites, exhibited early postnatal death from respiratory arrest and a marked absence of cervical spinal neuron respiratory discharges. mice also displayed disrupted lumbar spinal neuron locomotor rhythmogenesis and touch-evoked status epilepticus associated with markedly impaired KCC2-dependent Cl extrusion. These data identify a previously unknown phosphorylation-dependent KCC2 regulatory mechanism during CNS development that is essential for dynamic GABA-mediated inhibition and survival.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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16 MeSH Terms
Loss of flow responsive Tie1 results in Impaired
Aortic valve remodeling.
Qu X, Violette K, Sewell-Loftin MK, Soslow J, Saint-Jean L, Hinton RB, Merryman WD, Baldwin HS
(2019) Dev Biol 455: 73-84
MeSH Terms: Animals, Aortic Valve, Endothelial Cells, Extracellular Matrix, Female, Gene Expression Profiling, Gene Expression Regulation, Developmental, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Organogenesis, Pregnancy, Receptor, TIE-1, SOX9 Transcription Factor, Vascular Remodeling
Show Abstract · Added November 25, 2019
The mechanisms regulating endothelial cell response to hemodynamic forces required for heart valve development, especially valve remodeling, remain elusive. Tie1, an endothelial specific receptor tyrosine kinase, is up-regulated by oscillating shear stress and is required for lymphatic valve development. In this study, we demonstrate that valvular endothelial Tie1 is differentially expressed in a dynamic pattern predicted by disturbed flow during valve remodeling. Following valvular endocardial specific deletion of Tie1 in mice, we observed enlarged aortic valve leaflets, decreased valve stiffness and valvular insufficiency. Valve abnormalities were only detected in late gestation and early postnatal mutant animals and worsened with age. The mutant mice developed perturbed extracellular matrix (ECM) deposition and remodeling characterized by increased glycosaminoglycan and decreased collagen content, as well as increased valve interstitial cell expression of Sox9, a transcription factor essential for normal ECM maturation during heart valve development. This study provides the first evidence that Tie1 is involved in modulation of late valve remodeling and suggests that an important Tie1-Sox9 signaling axis exists through which disturbed flows are converted by endocardial cells to paracrine Sox9 signals to modulate normal matrix remodeling of the aortic valve.
Copyright © 2019. Published by Elsevier Inc.
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15 MeSH Terms
Serotonin transporter inhibition and 5-HT receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice.
Stewart A, Davis GL, Gresch PJ, Katamish RM, Peart R, Rabil MJ, Gowrishankar R, Carroll FI, Hahn MK, Blakely RD
(2019) Neuropsychopharmacology 44: 994-1006
MeSH Terms: Animals, Behavior, Animal, Cocaine, Conditioning, Classical, Disease Models, Animal, Dopamine, Dopamine Plasma Membrane Transport Proteins, Dopamine Uptake Inhibitors, Fluoxetine, Locomotion, Methylphenidate, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Neostriatum, Receptor, Serotonin, 5-HT2C, Serotonin Plasma Membrane Transport Proteins, Serotonin Uptake Inhibitors
Show Abstract · Added January 8, 2019
Dopamine (DA) signaling dysfunction is believed to contribute to multiple neuropsychiatric disorders including attention-deficit/hyperactivity disorder (ADHD). The rare DA transporter (DAT) coding substitution Ala559Val found in subjects with ADHD, bipolar disorder and autism, promotes anomalous DA efflux in vitro and, in DAT Val559 mice, leads to increased reactivity to imminent handling, waiting impulsivity, and enhanced motivation for reward. Here, we report that, in contrast to amphetamine and methylphenidate, which induce significant locomotor activation, cocaine administration to these mice elicits no locomotor effects, despite retention of conditioned place preference (CPP). Additionally, cocaine fails to elevate extracellular DA. Given that amphetamine and methylphenidate, unlike cocaine, lack high-affinity interactions with the serotonin (5-HT) transporter (SERT), we hypothesized that the lack of cocaine-induced hyperlocomotion in DAT Val559 mice arises from SERT blockade and augmented 5-HT signaling relative to cocaine actions on wildtype animals. Consistent with this idea, the SERT blocker fluoxetine abolished methylphenidate-induced locomotor activity in DAT Val559 mice, mimicking the effects seen with cocaine. Additionally, a cocaine analog (RTI-113) with greater selectivity for DAT over SERT retains locomotor activation in DAT Val559 mice. Furthermore, genetic elimination of high-affinity cocaine interactions at SERT in DAT Val559 mice, or specific inhibition of 5-HT receptors in these animals, restored cocaine-induced locomotion, but did not restore cocaine-induced elevations of extracellular DA. Our findings reveal a significant serotonergic plasticity arising in the DAT Val559 model that involves enhanced 5-HT signaling, acting independently of striatal DA release, capable of suppressing the activity of cocaine-sensitive motor circuits.
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19 MeSH Terms
Is dopamine transporter-mediated dopaminergic signaling in the retina a noninvasive biomarker for attention-deficit/ hyperactivity disorder? A study in a novel dopamine transporter variant Val559 transgenic mouse model.
Dai H, Jackson CR, Davis GL, Blakely RD, McMahon DG
(2017) J Neurodev Disord 9: 38
MeSH Terms: Animals, Attention Deficit Disorder with Hyperactivity, Biomarkers, Disease Models, Animal, Dopamine, Dopamine Plasma Membrane Transport Proteins, Electroretinography, Female, Male, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Retina, Vision, Ocular
Show Abstract · Added February 9, 2018
BACKGROUND - Dopamine (DA) is a critical neuromodulator in the retina. Disruption of retinal DA synthesis and signaling significantly attenuates light-adapted, electroretinogram (ERG) responses, as well as contrast sensitivity and acuity. As these measures can be detected noninvasively, they may provide opportunities to detect disease processes linked to perturbed DA signaling. Recently, we identified a rare, functional DA transporter (DAT, SLC6A3) coding substitution, Ala559Val, in subjects with attention-deficit/hyperactivity disorder (ADHD), demonstrating that DAT Val559 imparts anomalous DA efflux (ADE) with attendant physiological, pharmacological, and behavioral phenotypes. To understand the broader impact of ADE on ADHD, noninvasive measures sensitive to DAT reversal are needed.
METHODS - Here, we explored this question through ERG-based analysis of retinal light responses, as well as HPLC measurements of retinal DA in DAT Val559 mice.
RESULTS - Male mice homozygous (HOM) for the DAT Val559 variant demonstrated increased, light-adapted ERG b-wave amplitudes compared to wild type (WT) and heterozygous (HET) mice, whereas dark-adapted responses were indistinguishable across genotypes. The elevated amplitude of the photopic light responses in HOM mice could be mimicked in WT mice by applying D and D DA receptor agonists and suppressed in HOM mice by introducing D antagonist, supporting elevated retinal DA signaling arising from ADE. Following the challenge with amphetamine, WT exhibited an increase in light-adapted response amplitudes, while HOM did not. Total retinal DA content was similar across genotypes. Interestingly, female DAT Val559 HOM animals revealed no significant difference in photopic ERG responses when compared with WT and HET littermates.
CONCLUSIONS - These data reveal that noninvasive, in vivo evaluation of retinal responses to light can reveal physiological signatures of ADE, suggesting a possible approach to the segregation of neurobehavioral disorders based on the DAT-dependent control of DA signaling.
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14 MeSH Terms
Interleukin-22 drives nitric oxide-dependent DNA damage and dysplasia in a murine model of colitis-associated cancer.
Wang C, Gong G, Sheh A, Muthupalani S, Bryant EM, Puglisi DA, Holcombe H, Conaway EA, Parry NAP, Bakthavatchalu V, Short SP, Williams CS, Wogan GN, Tannenbaum SR, Fox JG, Horwitz BH
(2017) Mucosal Immunol 10: 1504-1517
MeSH Terms: Animals, Antibodies, Blocking, Colitis, Ulcerative, Colon, Colonic Neoplasms, DNA Breaks, Double-Stranded, DNA-Binding Proteins, Disease Models, Animal, Helicobacter Infections, Helicobacter hepaticus, Humans, Inflammation, Interleukins, Macrophages, Peritoneal, Mice, Mice, 129 Strain, Mice, Knockout, Neoplasms, Nitric Oxide, Nitric Oxide Synthase Type II
Show Abstract · Added April 15, 2019
The risk of colon cancer is increased in patients with Crohn's disease and ulcerative colitis. Inflammation-induced DNA damage could be an important link between inflammation and cancer, although the pathways that link inflammation and DNA damage are incompletely defined. RAG2-deficient mice infected with Helicobacter hepaticus (Hh) develop colitis that progresses to lower bowel cancer. This process depends on nitric oxide (NO), a molecule with known mutagenic potential. We have previously hypothesized that production of NO by macrophages could be essential for Hh-driven carcinogenesis, however, whether Hh infection induces DNA damage in this model and whether this depends on NO has not been determined. Here we demonstrate that Hh infection of RAG2-deficient mice rapidly induces expression of iNOS and the development of DNA double-stranded breaks (DSBs) specifically in proliferating crypt epithelial cells. Generation of DSBs depended on iNOS activity, and further, induction of iNOS, the generation of DSBs, and the subsequent development of dysplasia were inhibited by depletion of the Hh-induced cytokine IL-22. These results demonstrate a strong association between Hh-induced DNA damage and the development of dysplasia, and further suggest that IL-22-dependent induction of iNOS within crypt epithelial cells rather than macrophages is a driving force in this process.
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Effects of deletion on body weight and cholesterol in mice.
Boortz KA, Syring KE, Pound LD, Mo H, Bastarache L, Oeser JK, McGuinness OP, Denny JC, O'Brien RM
(2017) J Mol Endocrinol 58: 127-139
MeSH Terms: Animals, Blood Glucose, Body Weight, Cholesterol, Diet, High-Fat, Fasting, Female, Gene Deletion, Gene Expression, Genetic Association Studies, Genetic Background, Glucose Tolerance Test, Glucose-6-Phosphatase, Insulin, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Pancreas, Polymorphism, Single Nucleotide
Show Abstract · Added March 14, 2018
Genome-wide association study (GWAS) data have linked the gene to variations in fasting blood glucose (FBG). encodes an islet-specific glucose-6-phosphatase catalytic subunit that forms a substrate cycle with the beta cell glucose sensor glucokinase. This cycle modulates the glucose sensitivity of insulin secretion and hence FBG. GWAS data have not linked to variations in body weight but we previously reported that female C57BL/6J -knockout (KO) mice were lighter than wild-type littermates on both a chow and high-fat diet. The purpose of this study was to compare the effects of deletion on FBG and body weight in both chow-fed and high-fat-fed mice on two other genetic backgrounds. FBG was reduced in KO mice largely independent of gender, genetic background or diet. In contrast, the effect of deletion on body weight was markedly influenced by these variables. Deletion of conferred a marked protection against diet-induced obesity in male mixed genetic background mice, whereas in 129SvEv mice deletion of had no effect on body weight. deletion also reduced plasma cholesterol levels in a manner dependent on gender, genetic background and diet. An association between and plasma cholesterol was also observed in humans through electronic health record-derived phenotype analyses. These observations suggest that the action of G6PC2 on FBG is largely independent of the influences of environment, modifier genes or epigenetic events, whereas the action of G6PC2 on body weight and cholesterol are influenced by unknown variables.
© 2017 Society for Endocrinology.
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21 MeSH Terms
IL-4/IL-13-mediated polarization of renal macrophages/dendritic cells to an M2a phenotype is essential for recovery from acute kidney injury.
Zhang MZ, Wang X, Wang Y, Niu A, Wang S, Zou C, Harris RC
(2017) Kidney Int 91: 375-386
MeSH Terms: Acute Kidney Injury, Animals, Cell Plasticity, Dendritic Cells, Diphtheria Toxin, Disease Models, Animal, Fibrosis, Genotype, Heparin-binding EGF-like Growth Factor, Interleukin-13, Interleukin-4, Janus Kinase 3, Kidney, Macrophages, Male, Mice, 129 Strain, Mice, Inbred BALB C, Mice, Knockout, Phenotype, Recovery of Function, Reperfusion Injury, STAT6 Transcription Factor, Signal Transduction, Time Factors
Show Abstract · Added April 26, 2017
Cytokines IL-4 and IL-13 play important roles in polarization of macrophages/dendritic cells to an M2 phenotype, which is important for recovery from acute kidney injury. Both IL-4 and IL-13 activate JAK3/STAT6 signaling. In mice with diphtheria toxin receptor expression in proximal tubules (selective injury model), a relatively selective JAK3 inhibitor, tofacitinib, led to more severe kidney injury, delayed recovery from acute kidney injury, increased inflammatory M1 phenotype markers and decreased reparative M2 phenotype markers of macrophages/dendritic cells, and development of more severe renal fibrosis after diphtheria toxin administration. Similarly, there was delayed recovery and increased tubulointerstitial fibrosis in these diphtheria toxin-treated mice following tamoxifen-induced deletion of both IL-4 and IL-13, with increased levels of M1 and decreased levels of M2 markers in the macrophages/dendritic cells. Furthermore, deletion of IL-4 and IL-13 led to a decrease of tissue reparative M2a phenotype markers but had no effect on anti-inflammatory M2c phenotype markers. Deletion of IL-4 and IL-13 also inhibited recovery from ischemia-reperfusion injury in association with increased M1 and decreased M2 markers and promoted subsequent tubulointerstitial fibrosis. Thus, IL-4 and IL-13 are required to effectively polarize macrophages/dendritic cells to an M2a phenotype and to promote recovery from acute kidney injury.
Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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24 MeSH Terms
Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor Hypofunction Are Reversed by the Novel M PAM VU6004256.
Grannan MD, Mielnik CA, Moran SP, Gould RW, Ball J, Lu Z, Bubser M, Ramsey AJ, Abe M, Cho HP, Nance KD, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW, Jones CK
(2016) ACS Chem Neurosci 7: 1706-1716
MeSH Terms: Action Potentials, Animals, Cholinergic Agents, Cognition Disorders, Conditioning, Psychological, Disease Models, Animal, Drug Evaluation, Preclinical, Fear, Gene Knockdown Techniques, Heterocyclic Compounds, 4 or More Rings, Long-Term Synaptic Depression, Male, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Nerve Tissue Proteins, Nootropic Agents, Prefrontal Cortex, Pyramidal Cells, Receptors, N-Methyl-D-Aspartate, Recognition, Psychology, Tissue Culture Techniques
Show Abstract · Added April 6, 2017
Abnormalities in the signaling of the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) within cortical and limbic brain regions are thought to underlie many of the complex cognitive and affective symptoms observed in individuals with schizophrenia. The M muscarinic acetylcholine receptor (mAChR) subtype is a closely coupled signaling partner of the NMDAR. Accumulating evidence suggests that development of selective positive allosteric modulators (PAMs) of the M receptor represent an important treatment strategy for the potential normalization of disruptions in NMDAR signaling in patients with schizophrenia. In the present studies, we evaluated the effects of the novel and highly potent M PAM, VU6004256, in ameliorating selective prefrontal cortical (PFC)-mediated physiologic and cognitive abnormalities in a genetic mouse model of global reduction in the NR1 subunit of the NMDAR (NR1 knockdown [KD]). Using slice-based extracellular field potential recordings, deficits in muscarinic agonist-induced long-term depression (LTD) in layer V of the PFC in the NR1 KD mice were normalized with bath application of VU6004256. Systemic administration of VU6004256 also reduced excessive pyramidal neuron firing in layer V PFC neurons in awake, freely moving NR1 KD mice. Moreover, selective potentiation of M by VU6004256 reversed the performance impairments of NR1 KD mice observed in two preclinical models of PFC-mediated learning, specifically the novel object recognition and cue-mediated fear conditioning tasks. VU6004256 also produced a robust, dose-dependent reduction in the hyperlocomotor activity of NR1 KD mice. Taken together, the current findings provide further support for M PAMs as a novel therapeutic approach for the PFC-mediated impairments in schizophrenia.
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23 MeSH Terms
BMP Antagonist Gremlin 2 Limits Inflammation After Myocardial Infarction.
Sanders LN, Schoenhard JA, Saleh MA, Mukherjee A, Ryzhov S, McMaster WG, Nolan K, Gumina RJ, Thompson TB, Magnuson MA, Harrison DG, Hatzopoulos AK
(2016) Circ Res 119: 434-49
MeSH Terms: Animals, Bone Morphogenetic Protein 2, Cells, Cultured, Cytokines, Endothelial Cells, Female, Humans, Inflammation, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myocardial Infarction, Myocytes, Cardiac, Proteins, Pyrazoles, Quinolines
Show Abstract · Added July 5, 2016
RATIONALE - We have recently shown that the bone morphogenetic protein (BMP) antagonist Gremlin 2 (Grem2) is required for early cardiac development and cardiomyocyte differentiation. Our initial studies discovered that Grem2 is strongly induced in the adult heart after experimental myocardial infarction (MI). However, the function of Grem2 and BMP-signaling inhibitors after cardiac injury is currently unknown.
OBJECTIVE - To investigate the role of Grem2 during cardiac repair and assess its potential to improve ventricular function after injury.
METHODS AND RESULTS - Our data show that Grem2 is transiently induced after MI in peri-infarct area cardiomyocytes during the inflammatory phase of cardiac tissue repair. By engineering loss- (Grem2(-/-)) and gain- (TG(Grem2)) of-Grem2-function mice, we discovered that Grem2 controls the magnitude of the inflammatory response and limits infiltration of inflammatory cells in peri-infarct ventricular tissue, improving cardiac function. Excessive inflammation in Grem2(-/-) mice after MI was because of overactivation of canonical BMP signaling, as proven by the rescue of the inflammatory phenotype through administration of the canonical BMP inhibitor, DMH1. Furthermore, intraperitoneal administration of Grem2 protein in wild-type mice was sufficient to reduce inflammation after MI. Cellular analyses showed that BMP2 acts with TNFα to induce expression of proinflammatory proteins in endothelial cells and promote adhesion of leukocytes, whereas Grem2 specifically inhibits the BMP2 effect.
CONCLUSIONS - Our results indicate that Grem2 provides a molecular barrier that controls the magnitude and extent of inflammatory cell infiltration by suppressing canonical BMP signaling, thereby providing a novel mechanism for limiting the adverse effects of excessive inflammation after MI.
© 2016 American Heart Association, Inc.
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19 MeSH Terms
Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function.
Margolis KG, Li Z, Stevanovic K, Saurman V, Israelyan N, Anderson GM, Snyder I, Veenstra-VanderWeele J, Blakely RD, Gershon MD
(2016) J Clin Invest 126: 2221-35
MeSH Terms: Animals, Autism Spectrum Disorder, Enteric Nervous System, Female, Gastrointestinal Motility, Gastrointestinal Tract, Genetic Variation, Humans, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Models, Animal, Neurogenesis, Pregnancy, Serotonin, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added August 31, 2018
Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4-mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation.
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