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1

The role of adhesion molecule CD44 in dendritic tree arborization

100%
Dzwonek J., Gorlewicz A., Konopka A., Swiech L., Jaworski J., Wilczynski G.
Acta Neurobiologiae Experimentalis
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2011
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tom 71
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nr S
Dendritic arborization patterns define neuronal subtypes, and have important functional implications, determining how signals coming from individual synapses are integrated. Developing dendrites of neurons are responsive to extrinsic signals. Although several secreted proteins, cell surface receptors and adhesion molecules have been recently shown to be involved in dendrite morphogenesis, the role of extracellular matrix (ECM) components and molecular mechanisms of signal transduction from ECM to the neuronal cells involved in these processes are still poorly understood. The main component of the ECM in the brain is hyaluronan (HA). The major receptor for hyaluronan is CD44 adhesion molecule which mediates the response of cells to their extracellular microenvironment. The aim of this study was to investigate the role of CD44 in regulation of dendritic tree arborization. First, we examined the expression pattern of CD44 at the protein and RNA level in the rat brain by immunohistochemical, in situ hybridization and in situ PCR assays. All our experimental approaches clearly point to the neuronal localization of CD44, in addition to widely accepted presence in glia. Next, we investigated the role of CD44 in the hippocampal neurons cultured in vitro using the shRNA technology and anti-CD44 function-blocking antibody. The morphometric analysis show that cells with diminished expression of CD44 have more complex dendritic tree then control cells. Moreover, we have shown that treatment of neuronal cells with CD44 blocking antibody caused activation of small Rho GTPases (Cdc42, Rac1 and RhoA), which were previously shown to regulate dendritic tree arborization. These observations indicate that the members of small Rho GTPase family can be downstream effectors of CD44 in neuronal cells. The results of our experiments point to the importance of CD44 protein for the development of dendritic tree.
2

Neurogenesis and behavioral strategies in ICER overexpressing rats

84%
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.
3

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

84%
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.
4

CD44-ErbB receptor interaction studied by fluorescence resonance energy transfer analysis using fluorescence lifetime imaging microscopy

68%
Wlodarczyk J., Gorlewicz A., Wilczek E., Gawlak M., Cabaj A., Majczynski H., Nestarowicz K., Herbik M., Grieb P., Slawinska U., Kaczmarek L., Wilczynski G.
Acta Neurobiologiae Experimentalis
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2009
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tom 69
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nr 3
CD44 is a multifunctional cell surface glycoprotein which regulates cell-cell and cell-matrix interactions in a variety of tissues. CD44 was implicated in the development of peripheral nerves, functioning as a coreceptor for ErbB class of growth factor receptors. However, it is not known whether CD44-ErbB interaction may occur at the adult peripheral synapses. Here we studied, using Fluorescence Lifetime Imaging Microscopy, the proximity between CD44 and ErbB3 at the rat neuromuscular junction (NMJ). This was performed in muscle sections co-immunostained for CD44 and ErbB3, using secondary antibodies coupled to Alexa488 and Alexa647 respectively. Neuromuscular junctions were visualized using Alexa555-bound α-BT. The FRET between Alexa488 (donor) and Alexa647 (acceptor) was judged by measuring an accompanying changes in the donor fl uorescence lifetime. We found that the mean fl uorescence lifetime of the donor fl uorophore labeling CD44 protein was considerably shorter over the NMJ than in nonsynaptic sites. Then we compared normal rat muscle to the muscle affected by denervation in the transgenic model of amyotrophic lateral sclerosis (ALS). Importantly, ALS-like neurodegeneration resulted in signifi cant increase in molecular proximity of CD44 and ErbB3 at the NMJ. The specifi c complex formation between the two proteins was confi rmed using immunoprecipitation analysis. Our study provides novel data on the molecular architecture of the neuromuscular synapse in both health and disease.
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