TY  - JOUR
AU  - Moreno, Natalia
AU  - Schmidt, Christin
AU  - Ahlfeld, Julia
AU  - Pöschl, Julia
AU  - Dittmar, Stefanie
AU  - Pfister, Stefan
AU  - Kool, Marcel
AU  - Kerl, Kornelius
AU  - Schüller, Ulrich
TI  - Loss of Smarc proteins impairs cerebellar development.
JO  - The journal of neuroscience
VL  - 34
IS  - 40
SN  - 0270-6474
CY  - Washington, DC
PB  - Soc.44027
M1  - DKFZ-2017-00550
SP  - 13486-13491
PY  - 2014
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  - Atoh1 protein, mouse (NLM Chemicals)
KW  - Basic Helix-Loop-Helix Transcription Factors (NLM Chemicals)
KW  - Chromosomal Proteins, Non-Histone (NLM Chemicals)
KW  - Glial Fibrillary Acidic Protein (NLM Chemicals)
KW  - Nuclear Proteins (NLM Chemicals)
KW  - SMARCB1 Protein (NLM Chemicals)
KW  - Smarcb1 protein, mouse (NLM Chemicals)
KW  - Transcription Factors (NLM Chemicals)
KW  - Wnt Proteins (NLM Chemicals)
KW  - Green Fluorescent Proteins (NLM Chemicals)
KW  - Smarca4 protein, mouse (NLM Chemicals)
KW  - DNA Helicases (NLM Chemicals)
KW  - Phosphopyruvate Hydratase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25274825
DO  - DOI:10.1523/JNEUROSCI.2560-14.2014
UR  - https://inrepo02.dkfz.de/record/119959
ER  -