Kv10.1 (Eag1), member of the Kv10 family of voltage-gated potassium channels, is preferentially expressed in adult brain. The aim of the present study was to unravel the functional role of Kv10.1 in the brain by generating knockout mice, where the voltage sensor and pore region of Kv10.1 was removed to render non-functional proteins through deletion of exon 7 of the KCNH1 gene using the 3 Lox P strategy. Kv10.1-deficient mice show no obvious alterations during embryogenesis and develop normally to adulthood; cortex, hippocampus and cerebellum appear anatomically normal. Other tests, including general health screen, sensorimotor functioning and gating, anxiety, social behaviour, learning and memory did not show any functional aberrations in Kv10.1 null mice. Kv10.1 null mice display mild hyperactivity and longer-lasting haloperidol-induced catalepsy, but there was no difference between genotypes in amphetamine sensitisation and withdrawal, reactivity to apomorphine and haloperidol in the prepulse inhibition tests or to antidepressants in the haloperidol-induced catalepsy. Furthermore, electrical properties of Kv10.1 in cerebellar Purkinje cells did not show any difference between genotypes. Bearing in mind that Kv10.1 is overexpressed in over 70% of all human tumours and that its inhibition leads to a reduced tumour cell proliferation, the fact that deletion of Kv10.1 does not show a marked phenotype is a prerequisite for utilising Kv10.1 blocking and/or reduction techniques, such as siRNA, to treat cancer.
Behavioural and functional characterization of Kv10.1 (Eag1) knockout mice.
Specimen part
View SamplesNeuronal migration disorders such as lissencephaly and subcortical band heterotopia (SBH) are associated with epilepsy and intellectual disability. Doublecortin (DCX), LIS1 and alpha1-tubulin (TUBA1A), are mutated in these disorders, however corresponding mouse mutants do not show heterotopic neurons in the neocortex. On the other hand, the spontaneously arisen HeCo mouse mutant displays this phenotype. The study of this model reveals novel mechanisms of heterotopia formation. While, HeCo neurons migrate at the same speed as WT, abnormally distributed dividing progenitors were found throughout the cortical wall from E13. Through genetic studies we identified Eml1 as the mutant gene in HeCo mice. No full length transcripts of Eml1 were identified due to a retrotransposon insertion in an intron. Re-expression of Eml1, coding for a microtubule-associated protein, rescues the HeCo progenitor phenotype. We further show that EML1 is mutated in giant ribbon-like heterotopia in human. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human.
Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Metabolomic Identification of Subtypes of Nonalcoholic Steatohepatitis.
Age, Specimen part, Treatment
View SamplesMethionine adenosyltransferase (MAT) enzymes generate SAMe (S-adenosylmethionine), the main biological methyl donor. There are two MAT encoding genes in mammals (Mat1a and Mat2a), which show different activities and cellular distribution. Mat1a encodes the enzyme mainly expressed in normal liver. Mat1a ablation in mice results in the spontaneous development of non-alcoholic steatohepatitis (NASH). We observed that SAMe depletion in Mat1a KO mice had three main effects on hepatic lipid metabolism: 1) impaired TG (triglyceride) export via VLDL; 2) impaired mitochondrial FA (fatty acid) oxidation (as evidenced by membrane depolarization, downregulation of Phb1 (prohibitin 1, a mitochondrial chaperone protein) and Mcj/Dnajc15 (endogenous mitochondrial repressor of respiratory chain), and accumulation of long-chain acylcarnitines); and 3) increased FA uptake. The convergence of these three factors induced TG accumulation in LD (lipid droplets). LD expansion confronts hepatocytes with a high demand of PC (phosphatidylcholine) molecules to cover the LD surface since other phospholipids, such as PE (phosphatidylethanolamine), cannot stabilize LD and prevent coalescence. In Mat1a KO this situation is aggravated, since SAMe-dependent PC synthesis via PE methylation is decreased, the PC/PE ratio reduced and mitochondrial FA oxidation impaired. To put a brake to this drain of PC molecules to LD, FA are rerouted in Mat1a KO mice liver to other catabolic (endoplasmic reticulum and peroxisome oxidation) and biosynthetic (ceramides synthesis) pathways, causing oxidative stress, inflammation and fibrosis. SAMe treatment for two months in 8-9 month old Mat1a KO mice ameliorated mitochondrial dysfunction (reduces membrane depolarization, improves Phb1 and Mcj expression, and increases SAMe transport to mitochondria) improving FA oxidation efficiency (FA and acylcarnitine levels decrease), which results in a drastic reduction in TG accumulation. SAMe treatment in Mat1a KO mice resulted in more PC available for proper membrane function, improving liver lipid homeostasis, histology (H&E, Sudan red, Sirius red) and liver injury (ALT, AST).
Metabolomic Identification of Subtypes of Nonalcoholic Steatohepatitis.
Age, Specimen part
View SamplesAnxA4 expression is increased in H. pylori associated tumors. Moreover, in renal-cell cancer, AnxA4 increases tumor cell dissemination and promotes cell migration, and in colorectal cancer, it is identified as a potential diagnostic marker. How AnxA4 might be involved in tumorgenesis has remained unclear.
Revealing the molecular mechanism of gastric cancer marker annexin A4 in cancer cell proliferation using exon arrays.
Cell line, Treatment
View SamplesWe used microarrays to determine the expression profile of the P. aeruginosa creBC mutant regarding its parental wild type strain PAO1.
The Pseudomonas aeruginosa CreBC two-component system plays a major role in the response to β-lactams, fitness, biofilm growth, and global regulation.
Treatment
View SamplesWe reported that both conventional and adipose-specific Naa10p deletions in mice result in increased energy expenditure, thermogenesis, beige adipocyte differentiation and activation. Mechanistically, Naa10p acetylates the N-terminus of Pgc1α and prevents it from interacting with Ppar𝛾 to activate key genes, such as Ucp1, involved in beige adipocyte function. We used microarrays to profile the gene expression changes by Naa10p KO in inguinal white adipose tissues (iWATs) derived from mice fed with high fat diet for 15 weeks.
Naa10p Inhibits Beige Adipocyte-Mediated Thermogenesis through N-α-acetylation of Pgc1α.
Sex, Specimen part
View SamplesThe elevation of guanine nucleotide binding protein alpha 12 (G12) expression is highly associated with tumor invasiveness in several human cancers. We used an siRNA strategy to deplete G12 in oral squamous cell carcinoma (OSCC) cells and analyze the transcriptome profile by the Affymetrix Human Exon 1.0 ST platform.
Gα₁₂ drives invasion of oral squamous cell carcinoma through up-regulation of proinflammatory cytokines.
Sex, Specimen part, Cell line
View SamplesThis study focus on the expression signature between tumor and adjacent normal tissues.
Protein arginine methyltransferase 5 is a potential oncoprotein that upregulates G1 cyclins/cyclin-dependent kinases and the phosphoinositide 3-kinase/AKT signaling cascade.
Age
View SamplesA lung cancer cell model of invasive transformation was developed to select progressively invasive cell populations from a parental cell line of human lung adenocarcinoma, CL1. Five progressive sub-clones namely, CL1-1, CL1-2, CL1-3 CL1-4, and CL1-5 were selected using transwell and displayed increasing invasion potential (Chu et al, 1997).
Fucosyltransferase 8 as a functional regulator of nonsmall cell lung cancer.
Specimen part
View Samples