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, Jahrgang 34, Nr. 40, 01.10.2014, S. 13486-91.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -