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Loss of Smarc proteins impairs cerebellar development

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Loss of Smarc proteins impairs cerebellar development. / Moreno, Natalia; Schmidt, Christin; Ahlfeld, Julia; Pöschl, Julia; Dittmar, Stefanie; Pfister, Stefan M; Kool, Marcel; Kerl, Kornelius; Schüller, Ulrich.

In: J NEUROSCI, Vol. 34, No. 40, 01.10.2014, p. 13486-91.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Moreno, N, Schmidt, C, Ahlfeld, J, Pöschl, J, Dittmar, S, Pfister, SM, Kool, M, Kerl, K & Schüller, U 2014, 'Loss of Smarc proteins impairs cerebellar development', J NEUROSCI, vol. 34, no. 40, pp. 13486-91. https://doi.org/10.1523/JNEUROSCI.2560-14.2014

APA

Moreno, N., Schmidt, C., Ahlfeld, J., Pöschl, J., Dittmar, S., Pfister, S. M., Kool, M., Kerl, K., & Schüller, U. (2014). Loss of Smarc proteins impairs cerebellar development. J NEUROSCI, 34(40), 13486-91. https://doi.org/10.1523/JNEUROSCI.2560-14.2014

Vancouver

Moreno N, Schmidt C, Ahlfeld J, Pöschl J, Dittmar S, Pfister SM et al. Loss of Smarc proteins impairs cerebellar development. J NEUROSCI. 2014 Oct 1;34(40):13486-91. https://doi.org/10.1523/JNEUROSCI.2560-14.2014

Bibtex

@article{01c4460699a54f34a92a7170f2d28ef1,
title = "Loss of Smarc proteins impairs cerebellar development",
abstract = "SMARCA4 (BRG1) and SMARCB1 (INI1) are tumor suppressor genes that are crucially involved in the formation of malignant rhabdoid tumors, such as atypical teratoid/rhabdoid tumor (AT/RT). AT/RTs typically affect infants and occur at various sites of the CNS with a particular frequency in the cerebellum. Here, granule neurons and their progenitors represent the most abundant cell type and are known to give rise to a subset of medulloblastoma, a histologically similar embryonal brain tumor. To test how Smarc proteins influence the development of granule neurons and whether this population may serve as cellular origin for AT/RTs, we specifically deleted Smarca4 and Smarcb1 in cerebellar granule cell precursors. Respective mutant mice displayed severe ataxia and motor coordination deficits, but did not develop any tumors. In fact, they suffered from a severely hypoplastic cerebellum due to a significant inhibition of granule neuron precursor proliferation. Molecularly, this was accompanied by an enhanced activity of Wnt/β-catenin signaling that, by itself, is known to cause a nearly identical phenotype. We further used an hGFAP-cre allele, which deleted Smarcb1 much earlier and in a wider neural precursor population, but we still did not detect any tumor formation in the CNS. In summary, our results emphasize cell-type-dependent roles of Smarc proteins and argue against cerebellar granule cells and other progeny of hGFAP-positive neural precursors as the cellular origin for AT/RTs.",
keywords = "Age Factors, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Proliferation, Cells, Cultured, Cerebellum, Chromosomal Proteins, Non-Histone, DNA Helicases, Flow Cytometry, Gene Expression Regulation, Developmental, Glial Fibrillary Acidic Protein, Green Fluorescent Proteins, Mice, Mice, Transgenic, Mutation, Neural Stem Cells, Neurons, Nuclear Proteins, Phosphopyruvate Hydratase, Signal Transduction, Transcription Factors, Wnt Proteins, Journal Article, Research Support, Non-U.S. Gov't",
author = "Natalia Moreno and Christin Schmidt and Julia Ahlfeld and Julia P{\"o}schl and Stefanie Dittmar and Pfister, {Stefan M} and Marcel Kool and Kornelius Kerl and Ulrich Sch{\"u}ller",
note = "Copyright {\textcopyright} 2014 the authors 0270-6474/14/3413486-06$15.00/0.",
year = "2014",
month = oct,
day = "1",
doi = "10.1523/JNEUROSCI.2560-14.2014",
language = "English",
volume = "34",
pages = "13486--91",
journal = "J NEUROSCI",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "40",

}

RIS

TY - JOUR

T1 - Loss of Smarc proteins impairs cerebellar development

AU - Moreno, Natalia

AU - Schmidt, Christin

AU - Ahlfeld, Julia

AU - Pöschl, Julia

AU - Dittmar, Stefanie

AU - Pfister, Stefan M

AU - Kool, Marcel

AU - Kerl, Kornelius

AU - Schüller, Ulrich

N1 - Copyright © 2014 the authors 0270-6474/14/3413486-06$15.00/0.

PY - 2014/10/1

Y1 - 2014/10/1

N2 - SMARCA4 (BRG1) and SMARCB1 (INI1) are tumor suppressor genes that are crucially involved in the formation of malignant rhabdoid tumors, such as atypical teratoid/rhabdoid tumor (AT/RT). AT/RTs typically affect infants and occur at various sites of the CNS with a particular frequency in the cerebellum. Here, granule neurons and their progenitors represent the most abundant cell type and are known to give rise to a subset of medulloblastoma, a histologically similar embryonal brain tumor. To test how Smarc proteins influence the development of granule neurons and whether this population may serve as cellular origin for AT/RTs, we specifically deleted Smarca4 and Smarcb1 in cerebellar granule cell precursors. Respective mutant mice displayed severe ataxia and motor coordination deficits, but did not develop any tumors. In fact, they suffered from a severely hypoplastic cerebellum due to a significant inhibition of granule neuron precursor proliferation. Molecularly, this was accompanied by an enhanced activity of Wnt/β-catenin signaling that, by itself, is known to cause a nearly identical phenotype. We further used an hGFAP-cre allele, which deleted Smarcb1 much earlier and in a wider neural precursor population, but we still did not detect any tumor formation in the CNS. In summary, our results emphasize cell-type-dependent roles of Smarc proteins and argue against cerebellar granule cells and other progeny of hGFAP-positive neural precursors as the cellular origin for AT/RTs.

AB - SMARCA4 (BRG1) and SMARCB1 (INI1) are tumor suppressor genes that are crucially involved in the formation of malignant rhabdoid tumors, such as atypical teratoid/rhabdoid tumor (AT/RT). AT/RTs typically affect infants and occur at various sites of the CNS with a particular frequency in the cerebellum. Here, granule neurons and their progenitors represent the most abundant cell type and are known to give rise to a subset of medulloblastoma, a histologically similar embryonal brain tumor. To test how Smarc proteins influence the development of granule neurons and whether this population may serve as cellular origin for AT/RTs, we specifically deleted Smarca4 and Smarcb1 in cerebellar granule cell precursors. Respective mutant mice displayed severe ataxia and motor coordination deficits, but did not develop any tumors. In fact, they suffered from a severely hypoplastic cerebellum due to a significant inhibition of granule neuron precursor proliferation. Molecularly, this was accompanied by an enhanced activity of Wnt/β-catenin signaling that, by itself, is known to cause a nearly identical phenotype. We further used an hGFAP-cre allele, which deleted Smarcb1 much earlier and in a wider neural precursor population, but we still did not detect any tumor formation in the CNS. In summary, our results emphasize cell-type-dependent roles of Smarc proteins and argue against cerebellar granule cells and other progeny of hGFAP-positive neural precursors as the cellular origin for AT/RTs.

KW - Age Factors

KW - Animals

KW - Basic Helix-Loop-Helix Transcription Factors

KW - Cell Proliferation

KW - Cells, Cultured

KW - Cerebellum

KW - Chromosomal Proteins, Non-Histone

KW - DNA Helicases

KW - Flow Cytometry

KW - Gene Expression Regulation, Developmental

KW - Glial Fibrillary Acidic Protein

KW - Green Fluorescent Proteins

KW - Mice

KW - Mice, Transgenic

KW - Mutation

KW - Neural Stem Cells

KW - Neurons

KW - Nuclear Proteins

KW - Phosphopyruvate Hydratase

KW - Signal Transduction

KW - Transcription Factors

KW - Wnt Proteins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1523/JNEUROSCI.2560-14.2014

DO - 10.1523/JNEUROSCI.2560-14.2014

M3 - SCORING: Journal article

C2 - 25274825

VL - 34

SP - 13486

EP - 13491

JO - J NEUROSCI

JF - J NEUROSCI

SN - 0270-6474

IS - 40

ER -