scholarly journals Genetic ablation of Slc4a10 alters the expression pattern of transporters involved in solute movement in the mouse choroid plexus

2012 ◽  
Vol 302 (10) ◽  
pp. C1452-C1459 ◽  
Author(s):  
Helle Hasager Damkier ◽  
Jeppe Praetorius
Keyword(s):  
Choroid Plexus ◽  
Knockout Mice ◽  
Loss Of Function ◽  
Genetic Ablation ◽  
Aqp1 Expression ◽  
Molecular Machinery ◽  
Solute Movement ◽  
Basolateral Plasma Membrane ◽  
Cellular Polarization ◽  
Leaky Epithelium

Mutational changes of one transporter can have deleterious effects on epithelial function leaving the cells with the options of either compensating for the loss of function or dedifferentiating. Previous studies have shown that the choroid plexus epithelium (CPE) from mice lacking the Na+-dependent Cl−/HCO3− exchanger (NCBE) encoded by Slc4a10 leads to retargeting of the Na+/H+ exchanger 1 (NHE1) from the luminal to the basolateral plasma membrane. We hypothesized that disruption of NCBE, the main basolateral Na+ importer in the CPE, would lead to a compensatory increase in the abundance of other important transport proteins in this tissue. Aquaporin-1 (AQP1) abundance was 42.7% lower and Na,K-ATPase 36.4% lower in the CPE of Slc4a10 knockout mice, respectively. The NHE1 binding ezrin cytoskeleton appeared disrupted in Slc4a10 knockout mice, whereas no changes were observed in cellular polarization with respect to claudin-2 and appearance of luminal surface microvilli. The renal proximal tubule constitutes a leaky epithelium with high transport rate similar to CPE. Here, Slc4a10 knockout did not affect Na,K-ATPase or AQP1 expression. CPE from AQP1 knockout mice has a secretory defect similar to Slc4a10 mice. However, neither NCBE nor Na,K-ATPase expression was affected in CPE from AQP1 knockout mice. By contrast, the abundance of Na,K-ATPase and NBCe1 was decreased by 23 and 31.7%, respectively, in AQP1 knockout proximal tubules, while the NHE3 abundance was unchanged. In conclusion, CPE lacking NCBE seems to spare the molecular machinery involved in CSF secretion rather than compensate for the loss of the Na+ loader. Slc4a10 knockout seems to be more deleterious to CPE than AQP1 knockout.

scholarly journals Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis

2020 ◽  
Author(s):  
Benjamin Ng ◽  
Anissa A. Widjaja ◽  
Sivakumar Viswanathan ◽  
Jinrui Dong ◽  
Sonia P. Chothani ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Lung Fibroblasts ◽  
Loss Of Function ◽  
Wild Type ◽  
Reduced Body ◽  
Body Weights ◽  
Show Evidence ◽  
Similarities And Differences ◽  
The Impact

AbstractGenetic loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and craniosynostosis. The impact of genetic LOF in IL11 has not been characterized. We generated IL11-knockout (Il11-/-) mice, which are born in normal Mendelian ratios, have normal hematological profiles and are protected from bleomycin-induced lung fibro-inflammation. Noticeably, baseline IL6 levels in the lungs of Il11-/- mice are lower than those of wild-type mice and are not induced by bleomycin damage, placing IL11 upstream of IL6. Lung fibroblasts from Il11-/- mice are resistant to pro-fibrotic stimulation and show evidence of reduced autocrine IL11 activity. Il11-/- female mice are infertile. Unlike Il11ra1-/- mice, Il11-/- mice do not have a craniosynostosis-like phenotype and exhibit mildly reduced body weights. These data highlight similarities and differences between LOF in IL11 or IL11RA while establishing further the role of IL11 signaling in fibrosis and stromal inflammation.

scholarly journals Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

2015 ◽  
Vol 112 (10) ◽  
pp. 3056-3061 ◽  
Author(s):  
Jayendra Kumar Krishnaswamy ◽  
Arpita Singh ◽  
Uthaman Gowthaman ◽  
Renee Wu ◽  
Pavane Gorrepati ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Knockout Mice ◽  
T Cell Response ◽  
Inflammasome Activation ◽  
Nucleotide Exchange ◽  
Loss Of Function ◽  
Pyrin Domain ◽  
Proteomic Approach ◽  
Dendritic Cell Migration

Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naïve T cells, DCs must migrate to lymph nodes, yet the cellular programs responsible for this key step remain unclear. DC migration to lymph nodes and the subsequent T-cell response are disrupted in a mouse we recently described lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain containing 10); however, the mechanism by which this pattern recognition receptor governs DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10 knockout mice lack the guanine nucleotide exchange factor DOCK8 (dedicator of cytokinesis 8), which regulates cytoskeleton dynamics in multiple leukocyte populations; in humans, loss-of-function mutations in Dock8 result in severe immunodeficiency. Surprisingly, Nlrp10 knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole-exome sequencing. Consistent with our original report, NLRP3 inflammasome activation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8 function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8 via targeted deletion confirmed its absolute requirement for DC migration. Because mutations in Dock genes have been discovered in other mouse lines, we analyzed the diversity of Dock8 across different murine strains and found that C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. We conclude that DOCK8 is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function.

scholarly journals Autochthonous tumors driven by Rb1 loss have an ongoing requirement for the RBP2 histone demethylase

2018 ◽  
Vol 115 (16) ◽  
pp. E3741-E3748 ◽  
Author(s):  
Samuel K. McBrayer ◽  
Benjamin A. Olenchock ◽  
Gabriel J. DiNatale ◽  
Diana D. Shi ◽  
Januka Khanal ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Histone Demethylase ◽  
Retinoblastoma Gene ◽  
Loss Of Function ◽  
Genetic Ablation ◽  
Tumor Bearing ◽  
Human Cancers ◽  
Promising Strategy ◽  
Downstream Effectors ◽  
Slow Tumor Growth

Inactivation of the retinoblastoma gene (RB1) product, pRB, is common in many human cancers. Targeting downstream effectors of pRB that are central to tumorigenesis is a promising strategy to block the growth of tumors harboring loss-of-function RB1 mutations. One such effector is retinoblastoma-binding protein 2 (RBP2, also called JARID1A or KDM5A), which encodes an H3K4 demethylase. Binding of pRB to RBP2 has been linked to the ability of pRB to promote senescence and differentiation. Importantly, genetic ablation of RBP2 is sufficient to phenocopy pRB’s ability to induce these cellular changes in cell culture experiments. Moreover, germline Rbp2 deletion significantly impedes tumorigenesis in Rb1+/− mice. The value of RBP2 as a therapeutic target in cancer, however, hinges on whether loss of RBP2 could block the growth of established tumors as opposed to simply delaying their onset. Here we show that conditional, systemic ablation of RBP2 in tumor-bearing Rb1+/− mice is sufficient to slow tumor growth and significantly extend survival without causing obvious toxicity to the host. These findings show that established Rb1-null tumors require RBP2 for growth and further credential RBP2 as a therapeutic target in human cancers driven by RB1 inactivation.

scholarly journals Inhibition of Ihh Reverses Temporomandibular Joint Osteoarthritis via a PTH1R Signaling Dependent Mechanism

2019 ◽  
Vol 20 (15) ◽  
pp. 3797 ◽  
Author(s):  
Hongxu Yang ◽  
Mian Zhang ◽  
Qian Liu ◽  
Hongyun Zhang ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Temporomandibular Joint ◽  
Knockout Mice ◽  
Terminal Differentiation ◽  
In Vivo Model ◽  
Dental Occlusion ◽  
Deep Zone ◽  
Loss Of Function ◽  
Superficial Zone ◽  
Osteoarthritic Cartilage ◽  
Temporomandibular Joint Osteoarthritis

The temporomandibular joint (TMJ), which is biomechanically related to dental occlusion, is often insulted by osteoarthritis (OA). This study was conducted to clarify the relationship between Indian hedgehog (Ihh) and parathyroid hormone receptor 1 (PTH1R) signaling in modulating the enhanced chondrocyte terminal differentiation in dental stimulated TMJ osteoarthritic cartilage. A gain- and loss-of-function strategy was used in an in vitro model in which fluid flow shear stress (FFSS) was applied, and in an in vivo model in which the unilateral anterior cross-bite (UAC) stimulation was adopted. Ihh and PTH1R signaling was modulated through treating the isolated chondrocytes with inhibitor/activator and via deleting Smoothened (Smo) and/or Pth1r genes in mice with the promoter gene of type 2 collagen (Col2-CreER) in the tamoxifen-inducible pattern. We found that both FFSS and UAC stimulation promoted the deep zone chondrocytes to undergo terminal differentiation, while cells in the superficial zone were robust. We demonstrated that the terminal differentiation process in deep zone chondrocytes promoted by FFSS and UAC was mediated by the enhanced Ihh signaling and declined PTH1R expression. The FFSS-promoted terminal differentiation was suppressed by administration of the Ihh inhibitor or PTH1R activator. The UAC-promoted chondrocytes terminal differentiation and OA-like lesions were rescued in Smo knockout, but were enhanced in Pth1r knockout mice. Importantly, the relieving effect of Smo knockout mice was attenuated when Pth1r knockout was also applied. Our data suggest a chondrocyte protective effect of suppressing Ihh signaling in TMJ OA cartilage which is dependent on PTH1R signaling.

scholarly journals The transcriptional repressor complex FRS7-FRS12 regulates flowering time and growth in Arabidopsis

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Andrés Ritter ◽  
Sabrina Iñigo ◽  
Patricia Fernández-Calvo ◽  
Ken S. Heyndrickx ◽  
Stijn Dhondt ◽  
...  
Keyword(s):  
Flowering Time ◽  
Environmental Changes ◽  
Loss Of Function ◽  
Related Sequence ◽  
Photoperiodic Regulation ◽  
Repressor Complex ◽  
Molecular Machinery ◽  
Living Organisms ◽  
External Signals ◽  
Short Days

Abstract Most living organisms developed systems to efficiently time environmental changes. The plant-clock acts in coordination with external signals to generate output responses determining seasonal growth and flowering time. Here, we show that two Arabidopsis thaliana transcription factors, FAR1 RELATED SEQUENCE 7 (FRS7) and FRS12, act as negative regulators of these processes. These proteins accumulate particularly in short-day conditions and interact to form a complex. Loss-of-function of FRS7 and FRS12 results in early flowering plants with overly elongated hypocotyls mainly in short days. We demonstrate by molecular analysis that FRS7 and FRS12 affect these developmental processes in part by binding to the promoters and repressing the expression of GIGANTEA and PHYTOCHROME INTERACTING FACTOR 4 as well as several of their downstream signalling targets. Our data reveal a molecular machinery that controls the photoperiodic regulation of flowering and growth and offer insight into how plants adapt to seasonal changes.

scholarly journals Non-cell autonomous OTX2 transcription factor regulates anxiety-related behavior in the mouse

2019 ◽  
Author(s):  
C. Vincent ◽  
J. Gilabert-Juan ◽  
R. Gibel-Russo ◽  
D. Alvarez-Fischer ◽  
M.-O. Krebs ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Transcription Factor ◽  
Choroid Plexus ◽  
Dopaminergic Neurons ◽  
Elevated Plus Maze ◽  
Loss Of Function ◽  
Adult Mice ◽  
Plus Maze ◽  
Parvalbumin Interneurons ◽  
Important Regulator

SUMMARYThe Otx2 homeoprotein transcription factor is expressed in the dopaminergic neurons of the ventral tegmental area, a mesencephalic nucleus involved in the control of complex behaviors through its projections to limbic structures, including the ventral hippocampus, amygdala, nucleus accumbens and medial prefrontal cortex. We find adult mice heterozygous for Otx2 show anxiolysis-like phenotype in light-dark box and elevated plus maze paradigms. However, the number of dopaminergic neurons, the integrity of their axons, their projection patterns in target structures, and the amounts of dopamine and dopamine metabolites in targets structures were not modified. Because OTX2 is expressed by the choroid plexus, secreted into cerebrospinal fluid and transferred to parvalbumin interneurons of the cortex, hippocampus, and amygdala, we investigated if this phenotype could result from the decreased synthesis of OTX2 in the choroid plexus. Indeed, the anxiolysis-like phenotype was partially recapitulated in the Otx2+/AA and scFvOtx2tg/0 choroid-plexus dependent non-cell-autonomous OTX2 loss of function mouse models. Furthermore, the phenotype was reversed by the overexpression of Otx2 specifically in choroid plexus of adult Otx2 heterozygous mice. Taken together, OTX2 synthesis by the choroid plexus followed by its secretion into the cerebrospinal fluid is an important regulator of the anxiety phenotype in the mouse.

scholarly journals Canonical Wnt signaling exerts bidirectional control on choroid plexus epithelial development

2020 ◽  
Author(s):  
Arpan Parichha ◽  
Varun Suresh ◽  
Mallika Chatterjee ◽  
Aditya Kshirsagar ◽  
Lihi Ben-Reuven ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Choroid Plexus ◽  
Embryonic Stem ◽  
Mammalian Brain ◽  
Loss Of Function ◽  
Canonical Wnt Signaling ◽  
Constitutive Activation ◽  
Cortical Hem ◽  
And Function ◽  
Canonical Wnt

AbstractThe choroid plexus (CP) secretes cerebrospinal fluid and is critical for the development and function of the brain. In the telencephalon, the CP epithelium (CPe) arises from the Wnt- and Bmp- expressing cortical hem. We examined the role of canonical Wnt signaling in CPe development and report that the mouse and human embryonic CPe expresses molecules in this pathway. Either loss of function or constitutive activation of β-catenin, a key mediator of canonical Wnt signaling, causes a profound disruption of mouse CPe development. Loss of β-catenin results in a dysmorphic CPe, while constitutive activation of β-catenin causes a loss of CPe identity and a transformation of this tissue to a hippocampal-like identity. Aspects of this phenomenon are recapitulated in human embryonic stem cell (hESC)-derived organoids. Our results indicate that canonical Wnt signaling is required in a precisely regulated manner for normal CP development in the mammalian brain.

scholarly journals Oxytocin Regulates Synaptic Transmission in the Sensory Cortices in a Developmentally Dynamic Manner

2021 ◽  
Vol 15 ◽  
Author(s):  
Jing Zhang ◽  
Shu-Jing Li ◽  
Wanying Miao ◽  
Xiaodi Zhang ◽  
Jing-Jing Zheng ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Knockout Mice ◽  
Pyramidal Neurons ◽  
Neural Circuit ◽  
Brain Slices ◽  
Building Blocks ◽  
Sensory Experience ◽  
Conditional Knockout ◽  
Excitatory Synaptic Transmission ◽  
Loss Of Function

The development and stabilization of neuronal circuits are critical to proper brain function. Synapses are the building blocks of neural circuits. Here we examine the effects of the neuropeptide oxytocin on synaptic transmission in L2/3 pyramidal neurons of the barrel field of the primary somatosensory cortex (S1BF). We find that perfusion of oxytocin onto acute brain slices significantly increases the frequency of miniature excitatory postsynaptic currents (mEPSC) of S1BF L2/3 pyramidal neurons at P10 and P14, but reduces it at the later ages of P22 and P28; the transition occurs at around P18. Since oxytocin expression is itself regulated by sensory experience, we also examine whether the effects of oxytocin on excitatory synaptic transmission correlate with that of sensory experience. We find that, indeed, the effects of sensory experience and oxytocin on excitatory synaptic transmission of L2/3 pyramidal neurons both peak at around P14 and plateau around P18, suggesting that they regulate a specific form of synaptic plasticity in L2/3 pyramidal neurons, with a sensitive/critical period ending around P18. Consistently, oxytocin receptor (Oxtr) expression in glutamatergic neurons of the upper layers of the cerebral cortex peaks around P14. By P28, however, Oxtr expression becomes more prominent in GABAergic neurons, especially somatostatin (SST) neurons. At P28, oxytocin perfusion increases inhibitory synaptic transmission and reduces excitatory synaptic transmission, effects that result in a net reduction of neuronal excitation, in contrast to increased excitation at P14. Using oxytocin knockout mice and Oxtr conditional knockout mice, we show that loss-of-function of oxytocin affects baseline excitatory synaptic transmission, while Oxtr is required for oxytocin-induced changes in excitatory synaptic transmission, at both P14 and P28. Together, these results demonstrate that oxytocin has complex and dynamic functions in regulating synaptic transmission in cortical L2/3 pyramidal neurons. These findings add to existing knowledge of the function of oxytocin in regulating neural circuit development and plasticity.

scholarly journals The zebrafish grime mutant uncovers an evolutionarily conserved role for Tmem161b in the control of cardiac rhythm

2021 ◽  
Vol 118 (9) ◽  
pp. e2018220118
Author(s):  
Charlotte D. Koopman ◽  
Jessica De Angelis ◽  
Swati P. Iyer ◽  
Arie O. Verkerk ◽  
Jason Da Silva ◽  
...  
Keyword(s):  
Cardiac Arrhythmia ◽  
Knockout Mice ◽  
Cardiac Rhythm ◽  
Molecular Mechanisms ◽  
Calcium Oscillations ◽  
Loss Of Function ◽  
Excitable Cells ◽  
Growth And Survival ◽  
Developing Heart ◽  
Control Of Cardiac Rhythm

The establishment of cardiac function in the developing embryo is essential to ensure blood flow and, therefore, growth and survival of the animal. The molecular mechanisms controlling normal cardiac rhythm remain to be fully elucidated. From a forward genetic screen, we identified a unique mutant, grime, that displayed a specific cardiac arrhythmia phenotype. We show that loss-of-function mutations in tmem161b are responsible for the phenotype, identifying Tmem161b as a regulator of cardiac rhythm in zebrafish. To examine the evolutionary conservation of this function, we generated knockout mice for Tmem161b. Tmem161b knockout mice are neonatal lethal and cardiomyocytes exhibit arrhythmic calcium oscillations. Mechanistically, we find that Tmem161b is expressed at the cell membrane of excitable cells and live imaging shows it is required for action potential repolarization in the developing heart. Electrophysiology on isolated cardiomyocytes demonstrates that Tmem161b is essential to inhibit Ca2+ and K+ currents in cardiomyocytes. Importantly, Tmem161b haploinsufficiency leads to cardiac rhythm phenotypes, implicating it as a candidate gene in heritable cardiac arrhythmia. Overall, these data describe Tmem161b as a highly conserved regulator of cardiac rhythm that functions to modulate ion channel activity in zebrafish and mice.

scholarly journals Involvement of the Choroid Plexus in the Pathogenesis of Niemann-Pick Disease Type C

2021 ◽  
Vol 15 ◽  
Author(s):  
Lien Van Hoecke ◽  
Caroline Van Cauwenberghe ◽  
Kristina Dominko ◽  
Griet Van Imschoot ◽  
Elien Van Wonterghem ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Premature Death ◽  
Loss Of Function ◽  
Lipid Storage Disease ◽  
Niemann Pick Disease ◽  
Progressive Neurodegeneration ◽  
Type C ◽  
Niemann Pick

Niemann-Pick type C (NPC) disease, sometimes called childhood Alzheimer’s, is a rare neurovisceral lipid storage disease with progressive neurodegeneration leading to premature death. The disease is caused by loss-of-function mutations in the Npc1 or Npc2 gene which both result into lipid accumulation in the late endosomes and lysosomes. Since the disease presents with a broad heterogenous clinical spectrum, the involved disease mechanisms are still incompletely understood and this hampers finding an effective treatment. As NPC patients, who carry NPC1 mutations, have shown to share several pathological features with Alzheimer’s disease (AD) and we and others have previously shown that AD is associated with a dysfunctionality of the blood-cerebrospinal fluid (CSF) barrier located at choroid plexus, we investigated the functionality of this latter barrier in NPC1 pathology. Using NPC1–/– mice, we show that despite an increase in inflammatory gene expression in choroid plexus epithelial (CPE) cells, the blood-CSF barrier integrity is not dramatically affected. Interestingly, we did observe a massive increase in autophagosomes in CPE cells and enlarged extracellular vesicles (EVs) in CSF upon NPC1 pathology. Additionally, we revealed that these EVs exert toxic effects on brain tissue, in vitro as well as in vivo. Moreover, we observed that EVs derived from the supernatant of NPC1–/– choroid plexus explants are able to induce typical brain pathology characteristics of NPC1–/–, more specifically microgliosis and astrogliosis. Taken together, our data reveal for the first time that the choroid plexus and CSF EVs might play a role in the brain-related pathogenesis of NPC1.

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