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.
authors.affiliation: Institute of Molecular Tumor Biology, Westfalian-Wilhelms-University, D-48149 Münster, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Moreno
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Christin
authors.identifier: http://orcid.org/0000-0002-2225-0583
authors.initials: C
authors.lastname: Schmidt
authors.affiliation: Center for Neuropathology, Ludwig-Maximilians-University, D-81377 Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Ahlfeld
authors.affiliation: Center for Neuropathology, Ludwig-Maximilians-University, D-81377 Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Pöschl
authors.affiliation: Institute of Molecular Tumor Biology, Westfalian-Wilhelms-University, D-48149 Münster, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dittmar
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany, Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, D-69120 Heidelberg, Germany, and.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.affiliation: Institute of Molecular Tumor Biology, Westfalian-Wilhelms-University, D-48149 Münster, Germany, Department of Pediatric Hematology and Oncology, University Children's Hospital, Westfalian-Wilhelms-University, D-48149 Münster, Germany kornelius.kerl@ukmuenster.de ulrich.schueller@lmu.de.
authors.forename: Kornelius
authors.initials: K
authors.lastname: Kerl
authors.affiliation: Center for Neuropathology, Ludwig-Maximilians-University, D-81377 Munich, Germany, kornelius.kerl@ukmuenster.de ulrich.schueller@lmu.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
mesh_terms: D000367:Age Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000254:growth & development*; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency* / Q000235:genetics; D004265:DNA Helicases / Q000172:deficiency* / Q000235:genetics; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D058953:Neural Stem Cells / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D000071796:SMARCB1 Protein; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002868:Chromosomal Proteins, Non-Histone; D004265:DNA Helicases; D005904:Glial Fibrillary Acidic Protein; D049452:Green Fluorescent Proteins; D009687:Nuclear Proteins; D010751:Phosphopyruvate Hydratase; D000071796:SMARCB1 Protein; D014157:Transcription Factors; D051153:Wnt Proteins; C500943:Atoh1 protein, mouse; C513265:Smarcb1 protein, mouse; C513194:Smarca4 protein, mouse
keywords: AT/RT; Smarc; brain; cerebellum; development; tumor