title: Generation of a mouse model of atypical teratoid/rhabdoid tumor of the central nervous system through combined deletion of Snf5 and p53.
abstract: Malignant rhabdoid tumors arise in several anatomic locations and are associated with poor outcomes. In the brain, these tumors are known as atypical teratoid/rhabdoid tumors (AT/RT). While genetically engineered models for malignant rhabdoid tumors exist, none of them recapitulate AT/RT, for which preclinical models remain lacking. In the majority of AT/RT, LOH occurs at the genetic locus SNF5 (Ini1/BAF47/Smarcb1), which functions as a subunit of the SWI/SNF chromatin-remodeling complex and a tumor suppressor in familial and sporadic malignant rhabdoid tumors. Therefore, we generated mice in which Snf5 was ablated specifically in nestin-positive and/or glial fibrillary acid protein (GFAP)-positive progenitor cells of the developing central nervous system (CNS). Snf5 ablation in nestin-positive cells resulted in early lethality that could not be rescued by loss of p53. However, Snf5 ablation in GFAP-positive cells caused a neurodegenerative phenotype exacerbated by p53 loss. Notably, these double mutants exhibited AT/RT development, associated with an earlier failure in granule neuron migration in the cerebellum, reduced neuronal projections in the hippocampus, degeneration of the corpus callosum, and ataxia and seizures. Gene expression analysis confirmed that the tumors that arose in Snf5/p53 mutant mice were distinct from other neural tumors and most closely resembled human AT/RT. Our findings uncover a novel role for Snf5 in oligodendrocyte generation and survival, and they offer evidence of the first genetically engineered mouse model for AT/RT in the CNS.
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Cancer Pathobiology, The Children's Hospital of Philadelphia, Research Institute, Philadelphia, Pennsylvania. ngj@email.chop.edu currant@email.chop.edu.
authors.forename: Jessica M Y
authors.initials: JM
authors.lastname: Ng
authors.affiliation: Pathology Core Laboratory, The Children's Hospital of Philadelphia, Research Institute, Philadelphia, Pennsylvania.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martinez
authors.affiliation: Department of Neurology and Pediatrics, Division of Child Neurology The Children's Hospital of Philadelphia, Research Institute, Philadelphia, Pennsylvania.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Marsh
authors.affiliation: Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Research Institute, Philadelphia, Pennsylvania.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: The NAPCore Facility, The Children's Hospital of Philadelphia, Research Institute, Philadelphia, Pennsylvania.
authors.forename: Eric
authors.initials: E
authors.lastname: Rappaport
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Cancer Pathobiology, The Children's Hospital of Philadelphia, Research Institute, Philadelphia, Pennsylvania.
authors.forename: Mariarita
authors.initials: M
authors.lastname: Santi
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Cancer Pathobiology, The Children's Hospital of Philadelphia, Research Institute, Philadelphia, Pennsylvania. ngj@email.chop.edu currant@email.chop.edu.
authors.forename: Tom
authors.initials: T
authors.lastname: Curran
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D003337:Corpus Callosum / Q000473:pathology; D017353:Gene Deletion; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000235:genetics*; D064231:Nestin / Q000235:genetics; D058953:Neural Stem Cells / Q000378:metabolism; D009836:Oligodendroglia / Q000473:pathology; D018335:Rhabdoid Tumor / Q000235:genetics* / Q000473:pathology; D000071796:SMARCB1 Protein; D013724:Teratoma / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D005904:Glial Fibrillary Acidic Protein; C577485:Nes protein, mouse; D064231:Nestin; D000071796:SMARCB1 Protein; C513265:Smarcb1 protein, mouse; D016159:Tumor Suppressor Protein p53