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1

Nuclear Beta-catenin is constitutively present in postmitotic thalamic neurons due to reduced activity of Beta-catenin degradation complex

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Misztal K., Wisniewska M. B., Ambrozkiewicz M., Kuznicki J.
Acta Neurobiologiae Experimentalis
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2011
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tom 71
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nr 1
Wnt activation promotes β-catenin accumulation upon inhibition of β-catenin degradation. Stabilized β-catenin translocates to the nucleus where it triggers transcription of the Lef1/Tcf target genes. Wnt/β-catenin signaling is essential for nervous system development as well as division and maturation of neuronal progenitors in adult brain. We showed recently that nuclear β-catenin is abundant in vivo in non-dividing neurons of adult thalamus, where it is involved in gene transcription of CACNA1G gene (Wisniewska et al, J Neurosci, 2010). Here we demonstrate spontaneous accumulation of β-catenin in 40% of cultured thalamic neurons and lack of such accumulation in cortical neurons. This phenomenon does not depend on soluble factors produced by glia or cortical neurons, since neither conditioned medium of cortical cells nor glial cells co-culture affect the number of β-catenin positive cells. This suggests that nuclear localization of β-catenin in thalamic neurons is not a consequence of paracrine stimulation. We also observed that Wnt signaling inhibitor DKK1 had no major effect on the number of β-catenin positive thalamic neurons. Thus, autocrine Wnt stimulation is not responsible for nuclear β-catenin accumulation in these neurons. We analyzed expression of APC, AXIN1 and GSK3β that are involved in degradation of β-catenin and detected lower level of APC and GSK3β in thalamus when compared to other brain regions. Our observations support an idea that β-catenin accumulation is an intrinsic feature of thalamic neurons, independent on cellular environment of thalamic neurons and on Wnt stimulation. We propose that accumulation of β-catenin in thalamus is a result of reduced β-catenin degradation rate. This work is supported by “Health-Prot” Grant no 229676 and Polish MNiSW Grant no 4252/B/P01/2010/38.
2

Myelin, oligodendrocytes and axonal pathology in ST8SIA2minus/minus mice, a model for schizophrenia research

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Wisniewska M. B., Szewczyk L., Hildebrandt H., Kuznicki J.
Acta Neurobiologiae Experimentalis
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2015
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tom 75
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nr Supl.
Growing body of evidence implicates myelin and axon abnormalities in schizophrenia. Using a proteomic approach, we detected a decrease in myelin proteins in the hippocampus of St8sia2-/- mice that display behavioral and neuroanatomical features of schizophrenia. ST8SIA2 adds polysialic acid to neural cell adhesion molecule (NCAM), and this posttranslational modification is vital for development and plasticity in the brain. Polymorphisms in the ST8SIA2 gene and NCAM hyposialylation have been associated with schizophrenia. To gain an insight into the relationship between polysialylation state of NCAM and myelin we performed phenotypic analysis of St8sia2-/- mice, focusing on: myelin formation and maintenance, oligodendrocyte differentiation, and ultrastructure of axons. We applied several imaging techniques ranging from histological staining to electron microscopy, several immunodetection methods, and in vitro differentiation of oligodendrocyte precursors. Myelin formation was not delayed in the knockout mice, yet the levels of major myelin proteins were decreased from the early beginning (in 15-day-old mice) and it was accompanied by a lower number of oligodendrocytes. Moreover, in vitro differentiation of oligodendrocyte precursors was less efficient in the case of St8sia2-/- cells. Ultrastructure analysis of the nerve fibers showed thinning of the myelin sheath in 3-month-old mice. This phenotype was more severe in 8-month-old mice, with clear signs of axon degeneration and even lesions. We suppose that these late axonal pathologies are secondary to oligodendrocyte and myelin dysfunction. We conclude that the ST8SIA2-mediated polysialylation of NCAM plays a role in maintaining myelin and axonal integrity. The myelin phenotype in St8sia2-/- mice resembles white matter abnormalities in schizophrenia. ST8SIA2-deficient mice are a suitable model for better understanding schizophrenia-associated myelin and axonal pathology and to identify novel therapeutic targets.
3

Thalamic dissociated culture as a model to investigate Lefl/Tcf target genes in postmitotic neurons

100%
Misztal K., Wisniewska M. B., Kuznicki J.
Acta Neurobiologiae Experimentalis
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2007
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tom 67
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nr 3
4

Diverse roles of Lef1 in the development of thalamus, pretectum and optic tectum

88%
Brozko N., Krolak M., Nagalski A., MacDonald R., Wisniewska M. B.
Acta Neurobiologiae Experimentalis
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2017
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tom 77
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nr Suppl.1
INTRODUCTION: Lef1 is an effector of the canonical Wnt pathway that has been implicated in brain development at many stages. Lef1 is expressed specifically in the dorsal diencephalon and mesencephalon from the early stages onwards in many vertebrates. However, its role in the development of these brain parts has not been investigated so far. AIM(S): I used zebrafish as a model organism to examine the role of the widely expressed Lef1 in regulating the specification of neurons in distinct domains in the diencephalon and mesencephalon. METHOD(S): Firstly, I analyzed the spatiotemporal expression patterns of Lef1 proteins in zebrafish brain cryosections. Then I performed knockdowns of lef1 using Morpholinos, and analyzed the expression of markers that are specific for diverse progenitors (at stage 30hpf) and neurons (at stage 3dpf) in the brain. To this end I used fluorescent in situ hybridization (ISH) and visualized the larvae under confocal microscopy. RESULTS: Immunostaining revealed a strong expression of the Lef1 protein in the brain at 2dpf. ISH at the stage of progenitor domains (shh, dbx1a) showed that lef1 is not involved in their formation in diencephalon (thalamus – Th, pretectum – Pt) and mesencephalon (optic tectum – TeO). However, I observed serious impairments in expression of ascl1a and neurog1, genes characteristic for different classes of prospective neurons in the primordium of the Th, Pt and TeO. Because ascl1 is expressed in GABAergic progenitors, I hypothesized that Lef1 is involved in the specification of GABAergic neurons. I verified it at the stage of 3dpf and observed an expansion of the tcf7l2 expression that is a marker of the caudal Th, into the GABAergic rostral Th (nkx2.2a). Moreover I noted a depletion of GABAergic neurons in Pt and TeO. CONCLUSIONS: Concluding, my results implicate Lef1 in establishing the boundaries of the caudal part of Th and in the generation of GABAergic neurons in Pt and TeO. The mechanisms by which Lef1 participates in these events are yet to be understood. FINANCIAL SUPPORT: PRELUDIUM – 2013/09/N/ NZ3/01377, OPUS – 2015/19/B/NZ3/02949.
5

Role of the TCF7L2 transcription factor in regulating the development of thalamus and growth of thalamic axons

88%
Lipiec M., Kozinski K., Zajkowski T., Nagalski A., Wisniewska M. B.
Acta Neurobiologiae Experimentalis
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2017
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tom 77
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nr Suppl.1
6

Immunolocalization of STIM1 in the mouse brain

88%
Skibinska-Kijek A., Wisniewska M. B., Gruszczynska-Biegala J., Methner A., Kuznicki J.
Acta Neurobiologiae Experimentalis
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2009
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tom 69
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nr 4
Capacitative Calcium Entry (CCE) in neurons seems to depend, as in non-excitatory cells, on endoplasmic reticulum calcium sensors STIM1 or STIM2. We show localization of STIM1 in the mouse brain by immunohistochemistry with a specific antibody. STIM1 immunoreactivity has wide, but not uniform, distribution throughout the brain and is observed in neuropil and cells. The most intensive immunoreactivity is observed in Purkinje neurons of cerebellum. High/moderate levels of immunostaining are found in hippocampus, cerebral cortex and in cortico-medial amygdala, low in thalamus and basolateral amygdala. Co-staining with anti-NeuN antibody identify STIM1 immunopositive cells as neurons. Real time PCR demonstrates that Stim2 expression is 7-fold higher than that of Stim1 in hippocampus and 3-fold in other regions. Immunoblotting confirms that levels of STIMs vary in different brain regions. The data show that STIM1 and STIM2 are present in the brain, thus both can be involved in CCE, depending on neuronal type.
7

Looking for beta-catenin target genes in mature neurons

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Wisniewska M. B., Klejman M., Michowski W., Dabrowski M., Filipkowski R. K., Kuznicki J.
Acta Neurobiologiae Experimentalis
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2007
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tom 67
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nr 3
8

The transcription factor TCF7L2 governs postmitotic embryonic development of the thalamus and adult intrinsic excitability of thalamic neurons

64%
Lipiec M. A., Kozinski K., Zajkowski T., Dabrowski M., Chakraborty C., Urban-Ciecko J., Toval A., Ferran J. L., Nagalski A., Wisniewska M. B.
Acta Neurobiologiae Experimentalis
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2019
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tom 79
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nr Suppl.1
INTRODUCTION: The thalamus integrates sensory information and is involved in the selection of behavioral responses. This requires proper development of thalamic nuclei, thalamocortical connections, and electrophysiological properties of thalamic neurons. Molecular mechanisms of postmitotic thalamic differentiation and adult homeostasis were poorly characterized. Our studies show that both are regulated by the transcription factor TCF7L2. AIM(S): To determine the role of TCF7L2 in the development of thalamic cytoarchitecture, molecular anatomy, thalamocortical connections, and intrinsic excitability of thalamic neurons. METHOD(S): We examined mouse embryos (E18.5) with a total knockout of Tcf7l2, and adolescent/adult mice (P20‑P60) with thalamus‑specific, postnatal knockout of Tcf7l2. Embryonic brain slices were used for Nissl staining to visualize anatomical structures, in situ hybridization for gene expression analysis, immunohistochemistry to visualize axon fibers and diencephalic substructures, or thalamocortical neural tracts tracing with DiI. Comparative RNA‑seq analysis was performed on isolates from thalami of both mouse strains. Live brain slices from adolescent TCF7L2-deficent mice were used for in vitro patch‑clamp analysis of thalamic neurons. RESULTS: E18.5 Tcf7l2‑/‑ mice show changes in anatomical and molecular boundaries in diencephalon, fail to produce thalamocortical axons, and do not maintain the expression of main transcription factors that mark thalamic subregions. Postnatal TCF7L2‑deficent thalamic neurons show reduced burst and tonic spiking. CONCLUSIONS: Accordingly, RNA‑seq study revealed changes in the expression of their typical ion channels. TCF7L2 orchestrates a network of transcription factor genes to regulate postmitotic molecular differentiation, segregation of neurons, and axon path-finding in the thalamo‑habenular domain. Continuous expression of TCF7L2 in adult is required to establish proper intrinsic electrophysiological properties of thalamic neurons.
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