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8 results on '"Etemad, Solmaz"'

1. High Glycolytic Activity Enhances Stem Cell Reprogramming of Fahd1-KO Mouse Embryonic Fibroblasts

Author

Salti, Ahmad, Etemad, Solmaz, Cubero, Marta Suarez, Albertini, Eva, Kovacs-Szalka, Beata, Holzknecht, Max, Cappuccio, Elia, Cavinato, Maria, Edenhofer, Frank, and Dürr, Pidder Jansen

Subjects
Mice, Knockout, Neurons, QH301-705.5, Hydrolases, Induced Pluripotent Stem Cells, oxidative phosphorylation, reprogramming, iPSCs, Cell Differentiation, Fibroblasts, Cellular Reprogramming, DNA, Mitochondrial, Article, Cell Line, Mitochondria, Mice, Inbred C57BL, Mice, FAHD1, Animals, Biology (General), neuronal differentiation, Glycolysis, glycolytic activity
Abstract

Mitochondria play a key role in metabolic transitions involved in the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), but the underlying molecular mechanisms remain largely unexplored. To obtain new insight into the mechanisms of cellular reprogramming, we studied the role of FAH domain-containing protein 1 (FAHD1) in the reprogramming of murine embryonic fibroblasts (MEFs) into iPSCs and their subsequent differentiation into neuronal cells. MEFs from wild type (WT) and Fahd1-knock-out (KO) mice were reprogrammed into iPSCs and characterized for alterations in metabolic parameters and the expression of marker genes indicating mitochondrial biogenesis. Fahd1-KO MEFs showed a higher reprogramming efficiency accompanied by a significant increase in glycolytic activity as compared to WT. We also observed a strong increase of mitochondrial DNA copy number and expression of biogenesis marker genes in Fahd1-KO iPSCs relative to WT. Neuronal differentiation of iPSCs was accompanied by increased expression of mitochondrial biogenesis genes in both WT and Fahd1-KO neurons with higher expression in Fahd1-KO neurons. Together these observations establish a role of FAHD1 as a potential negative regulator of reprogramming and add additional insight into mechanisms by which FAHD1 modulates mitochondrial functions.

Published
2021

3. The juvenile myoclonic epilepsy mutant of the calcium channel β4 subunit displays normal nuclear targeting in nerve and muscle cells

Author

Etemad, Solmaz, Campiglio, Marta, Obermair, Gerald J, and Flucher, Bernhard E

Subjects
Cell Nucleus, Male, Neurons, Mice, Inbred BALB C, Muscle Cells, hippocampal neurons, Muscle Fibers, Skeletal, Myoclonic Epilepsy, Juvenile, Hippocampus, CaV β4 subunit, dysgenic myotubes, Protein Subunits, Protein Transport, voltage-gated Ca2+ channel, Mutation, Animals, Humans, Female, Mutant Proteins, Calcium Channels, CACNB4, Research Paper
Abstract

Voltage-gated calcium channels regulate gene expression by controlling calcium entry through the plasma membrane and by direct interactions of channel fragments and auxiliary β subunits with promoters and the epigenetic machinery in the nucleus. Mutations of the calcium channel β(4) subunit gene (CACNB4) cause juvenile myoclonic epilepsy in humans and ataxia and epileptic seizures in mice. Recently a model has been proposed according to which failed nuclear translocation of the truncated β(4) subunit R482X mutation resulted in altered transcriptional regulation and consequently in neurological disease. Here we examined the nuclear targeting properties of the truncated β(4b(1–481)) subunit in tsA-201 cells, skeletal myotubes, and in hippocampal neurons. Contrary to expectation, nuclear targeting of β(4b(1–481)) was not reduced compared with full-length β(4b) in any one of the three cell systems. These findings oppose an essential role of the β(4) distal C-terminus in nuclear targeting and challenge the idea that the nuclear function of calcium channel β(4) subunits is critically involved in the etiology of epilepsy and ataxia in patients and mouse models with mutations in the CACNB4 gene.

Published
2014

7. Differential Neuronal Targeting of a New and Two Known Calcium Channel β4 Subunit Splice Variants Correlates with Their Regulation of Gene Expression.

Author

Etemad, Solmaz, Obermair, Gerald J., Bindreither, Daniel, Benedetti, Ariane, Stanika, Ruslan, Di Biase, Valentina, Burtscher, Verena, Koschak, Alexandra, Kofler, Reinhard, Geley, Stephan, Wille, Alexandra, Lusser, Alexandra, Flockerzi, Veit, and Flucher, Bernhard E.

Subjects
*CALCIUM channels, *GENE expression, *GENETIC regulation, *NEUROTRANSMITTERS, *NEUROPHYSIOLOGY, *EPIGENETICS
Abstract

The β subunits of voltage-gated calcium channels regulate surface expression and gating of CaV1 and CaV2 α1 subunits and thus contribute to neuronal excitability, neurotransmitter release, and calcium-induced gene regulation. In addition, certain β subunits are targeted into the nucleus, where they interact directly with the epigenetic machinery. Whereas their involvement in this multitude of functions is reflected by a great molecular heterogeneity of β isoforms derived from four genes and abundant alternative splicing, little is known about the roles of individual β variants in specific neuronal functions. In the present study, an alternatively spliced β4 subunit lacking the variableNterminus (β4e ) is identified. It is highly expressed in mouse cerebellum and cultured cerebellar granule cells (CGCs) and modulates P/Q-type calcium currents in tsA201 cells and CaV2.1 surface expression in neurons. Compared with the other two known full-length β4 variants (β4a and β4b ), β4e is most abundantly expressed in the distal axon, but lacks nuclear-targeting properties. To determine the importance of nuclear targeting of β4 subunits for transcriptional regulation, we performed whole-genome expression profiling of CGCs from lethargic (β4-null) mice individually reconstituted with β4a, β4b, and β4e. Notably, the number of genes regulated by each β4 splice variant correlated with the rank order of their nuclear-targeting properties (β4bβ4a>β4e ). Together, these findings support isoform-specific functions of β4 splice variants in neurons, with β4b playing a dual role in channel modulation and gene regulation, whereas the newly detected β4e variant serves exclusively in calcium-channel-dependent functions. [ABSTRACT FROM AUTHOR]

Published
2014
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8. Differential neuronal targeting of a new and two known calcium channel β4 subunit splice variants correlates with their regulation of gene expression.

Author

Etemad S, Obermair GJ, Bindreither D, Benedetti A, Stanika R, Di Biase V, Burtscher V, Koschak A, Kofler R, Geley S, Wille A, Lusser A, Flockerzi V, and Flucher BE

Subjects
Amino Acid Sequence, Animals, Blotting, Western, Calcium Channels metabolism, Female, Hippocampus metabolism, Immunohistochemistry, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Molecular Sequence Data, Oligonucleotide Array Sequence Analysis, Patch-Clamp Techniques, Protein Isoforms genetics, Protein Isoforms metabolism, Protein Subunits genetics, Protein Subunits metabolism, Reverse Transcriptase Polymerase Chain Reaction, Calcium Channels genetics, Gene Expression genetics, Neurons metabolism
Abstract

The β subunits of voltage-gated calcium channels regulate surface expression and gating of CaV1 and CaV2 α1 subunits and thus contribute to neuronal excitability, neurotransmitter release, and calcium-induced gene regulation. In addition, certain β subunits are targeted into the nucleus, where they interact directly with the epigenetic machinery. Whereas their involvement in this multitude of functions is reflected by a great molecular heterogeneity of β isoforms derived from four genes and abundant alternative splicing, little is known about the roles of individual β variants in specific neuronal functions. In the present study, an alternatively spliced β4 subunit lacking the variable N terminus (β4e) is identified. It is highly expressed in mouse cerebellum and cultured cerebellar granule cells (CGCs) and modulates P/Q-type calcium currents in tsA201 cells and CaV2.1 surface expression in neurons. Compared with the other two known full-length β4 variants (β4a and β4b), β4e is most abundantly expressed in the distal axon, but lacks nuclear-targeting properties. To determine the importance of nuclear targeting of β4 subunits for transcriptional regulation, we performed whole-genome expression profiling of CGCs from lethargic (β4-null) mice individually reconstituted with β4a, β4b, and β4e. Notably, the number of genes regulated by each β4 splice variant correlated with the rank order of their nuclear-targeting properties (β4b > β4a > β4e). Together, these findings support isoform-specific functions of β4 splice variants in neurons, with β4b playing a dual role in channel modulation and gene regulation, whereas the newly detected β4e variant serves exclusively in calcium-channel-dependent functions.

Published
2014
Full Text
View/download PDF

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