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Gene-Edited Human Kidney Organoids Reveal Mechanisms of Disease in Podocyte Development.
Kim YK, Refaeli I, Brooks CR, Jing P, Gulieva RE, Hughes MR, Cruz NM, Liu Y, Churchill AJ, Wang Y, Fu H, Pippin JW, Lin LY, Shankland SJ, Vogl AW, McNagny KM, Freedman BS
(2017) Stem Cells 35: 2366-2378
MeSH Terms: Animals, Cell Adhesion, Cell Differentiation, Gene Editing, Humans, Kidney, Kidney Glomerulus, Mice, Organoids, Pluripotent Stem Cells, Podocytes, Sialoglycoproteins
Show Abstract · Added March 14, 2019
A critical event during kidney organogenesis is the differentiation of podocytes, specialized epithelial cells that filter blood plasma to form urine. Podocytes derived from human pluripotent stem cells (hPSC-podocytes) have recently been generated in nephron-like kidney organoids, but the developmental stage of these cells and their capacity to reveal disease mechanisms remains unclear. Here, we show that hPSC-podocytes phenocopy mammalian podocytes at the capillary loop stage (CLS), recapitulating key features of ultrastructure, gene expression, and mutant phenotype. hPSC-podocytes in vitro progressively establish junction-rich basal membranes (nephrin podocin ZO-1 ) and microvillus-rich apical membranes (podocalyxin ), similar to CLS podocytes in vivo. Ultrastructural, biophysical, and transcriptomic analysis of podocalyxin-knockout hPSCs and derived podocytes, generated using CRISPR/Cas9, reveals defects in the assembly of microvilli and lateral spaces between developing podocytes, resulting in failed junctional migration. These defects are phenocopied in CLS glomeruli of podocalyxin-deficient mice, which cannot produce urine, thereby demonstrating that podocalyxin has a conserved and essential role in mammalian podocyte maturation. Defining the maturity of hPSC-podocytes and their capacity to reveal and recapitulate pathophysiological mechanisms establishes a powerful framework for studying human kidney disease and regeneration. Stem Cells 2017;35:2366-2378.
© 2017 AlphaMed Press.
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MeSH Terms
Densin-180 Controls the Trafficking and Signaling of L-Type Voltage-Gated Ca1.2 Ca Channels at Excitatory Synapses.
Wang S, Stanika RI, Wang X, Hagen J, Kennedy MB, Obermair GJ, Colbran RJ, Lee A
(2017) J Neurosci 37: 4679-4691
MeSH Terms: Animals, Calcium Channels, L-Type, Calcium Signaling, Cerebral Cortex, Excitatory Postsynaptic Potentials, Ion Channel Gating, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons, Protein Transport, Sialoglycoproteins, Signal Transduction, Synapses
Show Abstract · Added April 26, 2017
Voltage-gated Ca1.2 and Ca1.3 (L-type) Ca channels regulate neuronal excitability, synaptic plasticity, and learning and memory. Densin-180 (densin) is an excitatory synaptic protein that promotes Ca-dependent facilitation of voltage-gated Ca1.3 Ca channels in transfected cells. Mice lacking densin (densin KO) exhibit defects in synaptic plasticity, spatial memory, and increased anxiety-related behaviors-phenotypes that more closely match those in mice lacking Ca1.2 than Ca1.3. Therefore, we investigated the functional impact of densin on Ca1.2. We report that densin is an essential regulator of Ca1.2 in neurons, but has distinct modulatory effects compared with its regulation of Ca1.3. Densin binds to the N-terminal domain of Ca1.2, but not that of Ca1.3, and increases Ca1.2 currents in transfected cells and in neurons. In transfected cells, densin accelerates the forward trafficking of Ca1.2 channels without affecting their endocytosis. Consistent with a role for densin in increasing the number of postsynaptic Ca1.2 channels, overexpression of densin increases the clustering of Ca1.2 in dendrites of hippocampal neurons in culture. Compared with wild-type mice, the cell surface levels of Ca1.2 in the brain, as well as Ca1.2 current density and signaling to the nucleus, are reduced in neurons from densin KO mice. We conclude that densin is an essential regulator of neuronal Ca1 channels and ensures efficient Ca1.2 Ca signaling at excitatory synapses. The number and localization of voltage-gated Ca Ca channels are crucial determinants of neuronal excitability and synaptic transmission. We report that the protein densin-180 is highly enriched at excitatory synapses in the brain and enhances the cell surface trafficking and postsynaptic localization of Ca1.2 L-type Ca channels in neurons. This interaction promotes coupling of Ca1.2 channels to activity-dependent gene transcription. Our results reveal a mechanism that may contribute to the roles of Ca1.2 in regulating cognition and mood.
Copyright © 2017 the authors 0270-6474/17/374679-13$15.00/0.
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15 MeSH Terms
A Novel Human Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors.
Stephenson JR, Wang X, Perfitt TL, Parrish WP, Shonesy BC, Marks CR, Mortlock DP, Nakagawa T, Sutcliffe JS, Colbran RJ
(2017) J Neurosci 37: 2216-2233
MeSH Terms: Animals, Autism Spectrum Disorder, Brain, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cells, Cultured, Cycloheximide, Dendrites, Disease Models, Animal, Embryo, Mammalian, Excitatory Postsynaptic Potentials, Exploratory Behavior, Female, Gene Expression Regulation, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Rats, Rats, Sprague-Dawley, Receptors, AMPA, Receptors, N-Methyl-D-Aspartate, Sialoglycoproteins, Synaptic Transmission
Show Abstract · Added February 2, 2017
Characterizing the functional impact of novel mutations linked to autism spectrum disorder (ASD) provides a deeper mechanistic understanding of the underlying pathophysiological mechanisms. Here we show that a Glu183 to Val (E183V) mutation in the CaMKIIα catalytic domain, identified in a proband diagnosed with ASD, decreases both CaMKIIα substrate phosphorylation and regulatory autophosphorylation, and that the mutated kinase acts in a dominant-negative manner to reduce CaMKIIα-WT autophosphorylation. The E183V mutation also reduces CaMKIIα binding to established ASD-linked proteins, such as Shank3 and subunits of l-type calcium channels and NMDA receptors, and increases CaMKIIα turnover in intact cells. In cultured neurons, the E183V mutation reduces CaMKIIα targeting to dendritic spines. Moreover, neuronal expression of CaMKIIα-E183V increases dendritic arborization and decreases both dendritic spine density and excitatory synaptic transmission. Mice with a knock-in CaMKIIα-E183V mutation have lower total forebrain CaMKIIα levels, with reduced targeting to synaptic subcellular fractions. The CaMKIIα-E183V mice also display aberrant behavioral phenotypes, including hyperactivity, social interaction deficits, and increased repetitive behaviors. Together, these data suggest that CaMKIIα plays a previously unappreciated role in ASD-related synaptic and behavioral phenotypes. Many autism spectrum disorder (ASD)-linked mutations disrupt the function of synaptic proteins, but no single gene accounts for >1% of total ASD cases. The molecular networks and mechanisms that couple the primary deficits caused by these individual mutations to core behavioral symptoms of ASD remain poorly understood. Here, we provide the first characterization of a mutation in the gene encoding CaMKIIα linked to a specific neuropsychiatric disorder. Our findings demonstrate that this ASD-linked mutation disrupts multiple CaMKII functions, induces synaptic deficits, and causes ASD-related behavioral alterations, providing novel insights into the synaptic mechanisms contributing to ASD.
Copyright © 2017 the authors 0270-6474/17/372217-18$15.00/0.
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25 MeSH Terms
Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids.
Freedman BS, Brooks CR, Lam AQ, Fu H, Morizane R, Agrawal V, Saad AF, Li MK, Hughes MR, Werff RV, Peters DT, Lu J, Baccei A, Siedlecki AM, Valerius MT, Musunuru K, McNagny KM, Steinman TI, Zhou J, Lerou PH, Bonventre JV
(2015) Nat Commun 6: 8715
MeSH Terms: Cell Differentiation, Clustered Regularly Interspaced Short Palindromic Repeats, Embryonic Stem Cells, Gene Knockout Techniques, Germ Layers, Humans, Kidney, Kidney Diseases, Models, Biological, Organoids, Pluripotent Stem Cells, Sialoglycoproteins
Show Abstract · Added September 12, 2016
Human-pluripotent-stem-cell-derived kidney cells (hPSC-KCs) have important potential for disease modelling and regeneration. Whether the hPSC-KCs can reconstitute tissue-specific phenotypes is currently unknown. Here we show that hPSC-KCs self-organize into kidney organoids that functionally recapitulate tissue-specific epithelial physiology, including disease phenotypes after genome editing. In three-dimensional cultures, epiblast-stage hPSCs form spheroids surrounding hollow, amniotic-like cavities. GSK3β inhibition differentiates spheroids into segmented, nephron-like kidney organoids containing cell populations with characteristics of proximal tubules, podocytes and endothelium. Tubules accumulate dextran and methotrexate transport cargoes, and express kidney injury molecule-1 after nephrotoxic chemical injury. CRISPR/Cas9 knockout of podocalyxin causes junctional organization defects in podocyte-like cells. Knockout of the polycystic kidney disease genes PKD1 or PKD2 induces cyst formation from kidney tubules. All of these functional phenotypes are distinct from effects in epiblast spheroids, indicating that they are tissue specific. Our findings establish a reproducible, versatile three-dimensional framework for human epithelial disease modelling and regenerative medicine applications.
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12 MeSH Terms
Characterization of a central Ca2+/calmodulin-dependent protein kinase IIalpha/beta binding domain in densin that selectively modulates glutamate receptor subunit phosphorylation.
Jiao Y, Jalan-Sakrikar N, Robison AJ, Baucum AJ, Bass MA, Colbran RJ
(2011) J Biol Chem 286: 24806-18
MeSH Terms: Animals, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calmodulin, Humans, Isoenzymes, Mice, Mutation, Phosphorylation, Protein Structure, Tertiary, Rats, Receptors, AMPA, Receptors, N-Methyl-D-Aspartate, Sialoglycoproteins, Swine, Xenopus Proteins, Xenopus laevis
Show Abstract · Added June 21, 2013
The densin C-terminal domain can target Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα) in cells. Although the C-terminal domain selectively binds CaMKIIα in vitro, full-length densin associates with CaMKIIα or CaMKIIβ in brain extracts and in transfected HEK293 cells. This interaction requires a second central CaMKII binding site, the densin-IN domain, and an "open" activated CaMKII conformation caused by Ca(2+)/calmodulin binding, autophosphorylation at Thr-286/287, or mutation of Thr-286/287 to Asp. Mutations in the densin-IN domain (L815E) or in the CaMKIIα/β catalytic domain (I205/206K) disrupt the interaction. The amino acid sequence of the densin-IN domain is similar to the CaMKII inhibitor protein, CaMKIIN, and a CaMKIIN peptide competitively blocks CaMKII binding to densin. CaMKII is inhibited by both CaMKIIN and the densin-IN domain, but the inhibition by densin is substrate-selective. Phosphorylation of a model peptide substrate, syntide-2, or of Ser-831 in AMPA receptor GluA1 subunits is fully inhibited by densin. However, CaMKII phosphorylation of Ser-1303 in NMDA receptor GluN2B subunits is not effectively inhibited by densin in vitro or in intact cells. Thus, densin can target multiple CaMKII isoforms to differentially modulate phosphorylation of physiologically relevant downstream targets.
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17 MeSH Terms
Ca2+-dependent facilitation of Cav1.3 Ca2+ channels by densin and Ca2+/calmodulin-dependent protein kinase II.
Jenkins MA, Christel CJ, Jiao Y, Abiria S, Kim KY, Usachev YM, Obermair GJ, Colbran RJ, Lee A
(2010) J Neurosci 30: 5125-35
MeSH Terms: Animals, Calcium, Calcium Channels, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cell Line, Cells, Cultured, Dendritic Spines, Hippocampus, Humans, Membrane Potentials, Mice, Mice, Inbred BALB C, Neurons, Rats, Sialoglycoproteins, Transfection
Show Abstract · Added March 20, 2014
Ca(v)1 (L-type) channels and calmodulin-dependent protein kinase II (CaMKII) are key regulators of Ca(2+) signaling in neurons. CaMKII directly potentiates the activity of Ca(v)1.2 and Ca(v)1.3 channels, but the underlying molecular mechanisms are incompletely understood. Here, we report that the CaMKII-associated protein densin is required for Ca(2+)-dependent facilitation of Ca(v)1.3 channels. While neither CaMKII nor densin independently affects Ca(v)1.3 properties in transfected HEK293T cells, the two together augment Ca(v)1.3 Ca(2+) currents during repetitive, but not sustained, depolarizing stimuli. Facilitation requires Ca(2+), CaMKII activation, and its association with densin, as well as densin binding to the Ca(v)1.3 alpha(1) subunit C-terminal domain. Ca(v)1.3 channels and densin are targeted to dendritic spines in neurons and form a complex with CaMKII in the brain. Our results demonstrate a novel mechanism for Ca(2+)-dependent facilitation that may intensify postsynaptic Ca(2+) signals during high-frequency stimulation.
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16 MeSH Terms
Developmentally regulated alternative splicing of densin modulates protein-protein interaction and subcellular localization.
Jiao Y, Robison AJ, Bass MA, Colbran RJ
(2008) J Neurochem 105: 1746-60
MeSH Terms: Alternative Splicing, Animals, Brain, Cell Line, Gene Expression Regulation, Developmental, Humans, Protein Interaction Domains and Motifs, Rats, Sialoglycoproteins, Subcellular Fractions
Show Abstract · Added June 21, 2013
Densin is a member of the leucine-rich repeat (LRR) and PDZ domain (LAP) protein family that binds several signaling molecules via its C-terminal domains, including calcium/calmodulin-dependent protein kinase II (CaMKII). In this study, we identify several novel mRNA splice variants of densin that are differentially expressed during development. The novel variants share the LRR domain but are either prematurely truncated or contain internal deletions relative to mature variants of the protein (180 kDa), thus removing key protein-protein interaction domains. For example, CaMKIIalpha coimmunoprecipitates with densin splice variants containing an intact C-terminal domain from lysates of transfected HEK293 cells, but not with variants that only contain N-terminal domains. Immunoblot analyses using antibodies to peptide epitopes in the N- and C- terminal domains of densin are consistent with developmental regulation of splice variant expression in brain. Moreover, putative splice variants display different subcellular fractionation patterns in brain extracts. Expression of green fluorescent protein (GFP)-fused densin splice variants in HEK293 cells shows that the LRR domain can target densin to a plasma membrane-associated compartment, but that the splice variants are differentially localized and have potentially distinct effects on cell morphology. In combination, these data show that densin splice variants have distinct functional characteristics suggesting multiple roles during neuronal development.
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10 MeSH Terms
Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms and gastric cancer: a meta-analysis.
Camargo MC, Mera R, Correa P, Peek RM, Fontham ET, Goodman KJ, Piazuelo MB, Sicinschi L, Zabaleta J, Schneider BG
(2006) Cancer Epidemiol Biomarkers Prev 15: 1674-87
MeSH Terms: Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Interleukin 1 Receptor Antagonist Protein, Interleukin-1, Minisatellite Repeats, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Sialoglycoproteins, Stomach Neoplasms
Show Abstract · Added March 5, 2014
BACKGROUND - Polymorphisms of interleukin-1B (IL1B) and its receptor antagonist (IL1RN) genes have been inconsistently associated with gastric cancer risk. We examined these associations by performing meta-analyses.
MATERIALS AND METHODS - Twenty-five studies testing the association between IL1B and/or IL1RN gene polymorphisms and gastric cancer were examined: 14 studies of IL1B-511, 14 studies of IL1B-31, 8 studies of IL1B+3954, and 23 studies of IL1RN. Overall and ethnicity-specific summary odds ratios and corresponding 95% confidence intervals for gastric cancer associated with these polymorphisms were estimated using fixed- and random-effects models. Heterogeneity and publication bias were evaluated.
RESULTS - IL1B-511T and IL1RN*2 were associated with gastric cancer risk in Caucasians, but not in Asians. For IL1B-511T, the association in Caucasians was stronger when intestinal-subtype and noncardia gastric cancer cases were examined. A nonsignificant trend was observed between IL1B-31C and gastric cancer in Caucasians. No significant association of IL1B+3954T and gastric cancer risk was detected. Studies with better methodologic characteristics reported stronger effects. There was no evidence of publication bias.
CONCLUSION - IL1B-511T is associated with gastric cancer susceptibility in Caucasians. The meta-analyses suggest that the conflicting results among studies may be explained by variation in allele frequencies among the ethnic groups and variation in tumor types, as well as by the methodologic quality of the studies.
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11 MeSH Terms
Clinical and echocardiographic correlates of plasma osteopontin in the community: the Framingham Heart Study.
Arnlöv J, Evans JC, Benjamin EJ, Larson MG, Levy D, Sutherland P, Siwik DA, Wang TJ, Colucci WS, Vasan RS
(2006) Heart 92: 1514-5
MeSH Terms: Biomarkers, Cardiovascular Diseases, Echocardiography, Female, Humans, Male, Middle Aged, Osteopontin, Risk Factors, Sex Factors, Sialoglycoproteins
Added April 15, 2014
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11 MeSH Terms
Plasminogen activator inhibitor-1 deficiency protects against aldosterone-induced glomerular injury.
Ma J, Weisberg A, Griffin JP, Vaughan DE, Fogo AB, Brown NJ
(2006) Kidney Int 69: 1064-72
MeSH Terms: Albuminuria, Aldosterone, Animals, Blood Pressure, Chemokine CCL2, Collagen, Fibronectins, Gene Expression, Glomerulonephritis, Hemodynamics, Kidney Glomerulus, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Myocardium, Nephrectomy, Osteopontin, Plasminogen Activator Inhibitor 1, RNA, Messenger, Sialoglycoproteins, Sodium
Show Abstract · Added December 10, 2013
This study tests the hypothesis that plasminogen activator inhibitor-1 (PAI-1) contributes to aldosterone-induced renal and cardiac injury. The effects of 12-week aldosterone (2.8 microg/day)/salt (1% drinking water) versus vehicle/salt on renal and cardiac histology and mRNA expression were determined in wild-type (WT) and PAI-1 deficient (PAI-1(-/-)) mice. Systolic blood pressure was similar in aldosterone-infused WT and PAI-1(-/-) mice until 12 weeks, when it was significantly higher in the WT mice. At 12 weeks, urine volume, sodium excretion, and sodium/potassium ratio were similarly increased in the two aldosterone-infused groups. In contrast, urine albumin excretion was greater in aldosterone-infused WT mice (mean+/-s.d.: 699.0+/-873.0 microg/24 h) compared to vehicle-infused WT (23.6+/-9.0 microg/24 h, P=0.003) or aldosterone-infused PAI-1(-/-) mice (131.6+/-110.6 microg/24 h, P=0.007). Aldosterone increased glomerular area to a greater extent in WT (4651+/-577 versus 3278+/-488 microm2/glomerulus in vehicle-infused WT, P<0.001) than in PAI-1(-/-) mice (3713+/-705 microm2/glomerulus, P=0.001 versus aldosterone-infused WT), with corresponding mesangial expansion. Renal collagen content was also increased in aldosterone-infused WT versus PAI-1(-/-) mice. In WT mice, aldosterone increased renal mRNA expression of PAI-1, collagen I, collagen III, osteopontin, fibronectin, monocyte chemoattractant protein-1 (MCP-1), and F4/80 (all P<0.05), but not transforming growth factor beta (TGF-beta). In PAI-1(-/-) mice, aldosterone increased renal expression of collagen I, osteopontin, fibronectin, and MCP-1, and tended to increase collagen III. Renal osteopontin expression was diminished in aldosterone-treated PAI-1(-/-) compared to aldosterone-treated WT mice (P=0.05). Aldosterone induced cardiac hypertrophy but not fibrosis in WT and PAI-1(-/-) mice. PAI-1 contributes to aldosterone-induced glomerular injury.
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23 MeSH Terms