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1

Inducible cAMP early repressor (ICER) isoforms and neuronal apoptosis in cortical in vitro culture

100%
Klejman A., Kaczmarek L.
Acta Neurobiologiae Experimentalis
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2006
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tom 66
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nr 4
CREB activation and CREB-dependent signaling pathways are crucial for neuronal survival. The term ICER (inducible cAMP early repressor) refers to four protein isoforms that are all endogenous, inducible antagonists of CREB. Jaworski and others (2003) have previously shown that one of those isoforms, ICER IIg, is highly expressed in apoptotic neurons in vitro and its overexpression evokes neuronal death. In this study we investigated the role of all four ICER isoforms in cortical neuronal culture, comparing their expression level in serum-deprived/MK-801-treated neurons and their pro-apoptotic properties towards transfected cortical neurons. We have found that all four isoforms are induced upon pro-apoptotic treatment, and also that each of them separately evokes neuronal cell death following cortical culture transfection with the genes. The most efficiently induced, as well as the most effective in evoking neuronal cell death, were both ICER Ig and IIg isoforms.
2

Lentiviral delivered siRNA against ICER protects primary cortical neurons from apoptosis caused by serum depriviation

81%
Klejman A., Bieganska K., Gierej D., Kaczmarek L.
Acta Neurobiologiae Experimentalis
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2009
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tom 69
|
nr 3
CREB activation and CREB-dependent signaling pathways are crucial for neuronal survival. The term ICER (inducible cAMP early repressor) refers to four protein isoforms that are all endogenous, inducible antagonists of CREB. It was previously shown, that all 4 ICER isoforms are induced upon pro-apoptotic treatment, and also that each of them separately evokes neuronal cell death in cortical culture transfected with these genes. The ICER proteins are believed to be strong repressors of Immediate Early Genes, which are involved in cell response to inter- and/or intra-cellular signals. Herein, we have applied the siRNA approach to silence ICER expression. Because ICERs are members of CREM family of proteins, sharing with them the gene sequence, only the small unique region for ICER was selected to design ICER-directed, specifi c siRNA. Indeed, we obtained functional siRNA capable of blocking ICERs but not affecting CREM proteins. With this tool, we have investigated if the ICER’s silencing protects neurons from apoptosis caused by either serum deprivation or excitotoxicity. Using the lentiviral vector, as a vehicle to deliver siRNA (shRNA) we have found that silencing of ICER mildly, although signifi cantly, protects primary cortical neurons from apoptosis caused by serum deprivation.
3

TDP-43 transgenic rat - animal model to study ALS and FTLD-U

81%
Koza P., Klejman A., Kaczmarek L.
Acta Neurobiologiae Experimentalis
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2011
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tom 71
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nr S
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) are characterized by mislocalisation and aggregation of predominantly nuclear TDP-43 protein. Our aim was to generate transgenic rats overexpressing wild type of human TDP-43 gene, fused with EGFP and under the control of synapsin promoter. Using lentiviral vectors as a tool for transgenesis, three founders carrying human TDP-43 gene were generated. The incorporation of transgene into genome was confirmed by specific PCR reaction and transgene copy number was determined by Real-Time quantitative PCR. Microscopic visualization and western blotting technique showed an abundant expression of GFP - fused TDP-43 protein in the brains of 3 months old animals. Notably, at this age no gross degeneration of neurons was detected. RotaRod test conducted on 5 months old transgenic rats showed no distinct motor deficits. At present we carry out behavioral analyses to verify whether animals exhibit cognitive impairments, which could possibly appear before any motor disorders. As neurodegeration occurs in ALS and FTLD-U patients in age-dependent manner, we plan to run further morphological and behavioral analyses on aging transgenic rats.
4

Neurogenesis and behavioral strategies in ICER overexpressing rats

51%
Klejman A., Janusz A., Kiryk-Jaskiewicz A., Gorlewicz A., Bieganska K., Jedynak P., Kaczmarek L., Konopka W.
Acta Neurobiologiae Experimentalis
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2019
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tom 79
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nr Suppl.1
INTRODUCTION: ICER (Inducible cAMP Early Repressor) is an effective endogenous repressor of CREB/ CREM/ATF transcription factors family, including its own expression. We have developed a Syn‑Flag‑ICER II transgenic rat line. In transgenic animals, we have surprisingly detected increased levels of mRNA for CREB or CREM transcription factors. We have also detected upregulation of CREB dependent miR‑132. Nerogenesis is a process of generation and maturation of newborn neurons into neuronal networks in the developing brain. We have found that ICER II overexpressing rats showed reduced hippocampal adult neurogenesis. The number of the SGZ BrdU positive cells was similar, but in the mature granular neurons layer, the number of BrdU positive cells was decreased when compared to control animals. One of the crucial elements enabling the incorporation of newborn neurons into neuronal network of the brain is the active reorganization of the extracellular matrix mostly by action of metalloproteinases. The most known for its activity in the brain is matrix metalloproteinase 9 (MMP-9), which is also one of the known targets of miR‑132. We have examined MMP-9 activity in the ICER overexpressing rat brain lysates, and we observed decreased activity of MMP‑9 in ICER mutants as compared to WT controls. RESULTS: We have also found that ICER rats with affected neurogenesis employ different learning strategies than their control littermates in the Morris Water Maze learning paradigm. The results of this behavioral tests indicate that transgenic rats didn’t differ from controls in their learning and memory capabilities, but they showed differences in strategies of finding the hidden platform. Male ICER rats more often were choosing imprecise strategies to find the platform than control males. CONCLUSIONS: Those results demonstrate that disruption of CREB dependent gene expression in neurons by overexpression of ICER affects adult neurogenesis and causes changes that affect discrete aspects of animal cognitive behavior.
5

Manipulation of CREB related gene expression in neurons influences adult neurogenesis and morris water maze strategies

51%
Janusz A., Klejman A., Kiryk-Jaskiewicz A., Gorlewicz A., Bieganska K., Jedynak P., Kaczmarek L., Konopka W.
Acta Neurobiologiae Experimentalis
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2017
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tom 77
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nr Suppl.1
INTRODUCTION: Active reorganization of extracellular matrix in the brain allows for growth of neuronal dendrites and axons which guarantees successful incorporation of new born neurons into neuronal network during adult neurogenesis in the hippocampus. Activity of surrounding neurons may affect adult neurogenesis. AIM(S): In order to test whether manipulation of CREB dependent gene expression in neurons and hence their activity will influence adult neurogenesis we have developed the Syn-Flag-ICER II transgenic rat line. The ICER (Inducible cAMP Early Repressor) is effective endogenous repressor of CREB/CREM/ATF transcription factors family. METHOD(S): BrdU labeling to asses a level of adult neurogenesis in the hippocampus qPCR for changes in transcription of CREB/CREM and related genes gelatin zymography to measure MMP9 activity Morris Water Maze spatial learning tests Patch Clamp RESULTS: ICER II overexpressing rats showed diminished hippocampal neurogenesis. We have observed a reduced number of mature BrdU positive cells in granular zone of hippocampus of transgenic rats, in comparison to control group. We have observed also that neurons of dentate gyrus demonstrate increased excitability. Paradoxically, we have detected increased levels of mRNA for CREB or CREM factors. Also CREB dependent miR-132 expression was upregulated in transgenic rats, which regulates expression of MMP-9 – extracellular matrix metalloproteinase. We have found the decreased activity of MMP9 in ICER overexpressing rats. Morris Water Maze tests didn’t show overall differences in rats learning and memory capabilities, however male ICER rats chose more often imprecise strategies to find hidden platform than control males. CONCLUSIONS: Obtained results indicate that CREB dependent gene expression in neurons regulates a set of genes e.g. miR-132 that may in turn regulate translation of proteins involved in remodeling of extracellular matrix and affect adult neurogenesis, what changes discrete aspects of animal cognitive behavior.
6

Chemotherapeutics-treated cancer cells display stem-like and senescent cell features

42%
Was H., Czarnecka J., Barszcz K., Kowalczyk A., Bernas T., Uzarowska E., Koza P., Klejman A., Piwocka K., Sikora E., Kaminska B.
Acta Biochimica Polonica
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2018
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tom 65
|
nr S2
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