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1

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

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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.
2

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

100%
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
3

Hypoglycaemic action of methylselenocysteine; in vitro an in vitro studies

100%
Kiersztan A., Baranska A., Lebiedzinska M., Nagalski A., Byla J.
Acta Biochimica Polonica
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2006
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tom 53
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nr Supplement 1
4

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

72%
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
|
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.
5

ST8SIA2 gene deficiency leads to aged-related axonal degeneration and weakening of myelin sheath

72%
Szewczyk L., Brozko N., Nagalski A., Liszewska E., Zawadzka M., Hildebrandt H., Kuznicki J., Wisniewska M.
Acta Neurobiologiae Experimentalis
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2015
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tom 75
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nr Supl.
BACKGROUND AND AIMS: This study was to investigate the involvement of ST8SIA2 in myelination of the brain. ST8SIA2 and its paralog ST8SIA4 synthesize polysialic acid chains (PSA) to NCAMs. Synthesis of PSA and its downregulation during brain development are crucial for a proper myelin formation. However, myelin forms normally in St8sia4-/- mice. So far, myelin-related phenotype of St8sia2-/- mice has not been investigated. METHODS: Mass-spectrometry, westernblot, myelin staining, immunostaining, electron microscopy RESULTS: Quantitative mass-spectrometry showed that the levels of myelin proteins MBP and PLP1 in the hippocampus are lower in adult St8sia2-/- mice than in control. Westernblot confirmed this result and revealed the same changes in cortical areas. Then, in order to determine the onset of the myelin impairment in the knockout mice, we labeled white matter in brain sections from mice at postnatal ages (P15 to P240) with Black Gold II, and showed that this phenotype develops with age. In agreement with this result, western blot analysis of major myelin proteins: PLP1, MBP, MOBP, MOG and CNPase, in the brain of mice from P15 to P90 revealed their lower levels in the knockouts, especially in the older mice. Electron microscopy revealed thinning of myelin sheath in the adult knockouts at P90 and P240, as well as abnormalities in axonal morphology and their degeneration at P240. Western blot revealed twofold lower levels of neurofilament proteins also suggesting axonopathy. CONCLUSIONS: ST8SIAII-mediated deficiency of polysialylation leads to axonal pathologies and their degeneration accompanied by myelin weakening. A decrease in polysialylated NCAM has been observed in postmortem schizophrenics brains, and the mice lacking the St8sia2 gene display schizophrenia-related behavior and anatomical abnormalities. We propose that myelin and axonal pathologies of schizophrenics might be a consequence of unsufficient level of polysialylation during development and in early adulthood.
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