title: Conditional KIAA1549:BRAF mice reveal brain region- and cell type-specific effects.
abstract: Low-grade brain tumors (pilocytic astrocytomas) that result from a genomic rearrangement in which the BRAF kinase domain is fused to the amino terminal of the KIAA1549 gene (KIAA1549:BRAF fusion; f-BRAF) commonly arise in the cerebellum of young children. To model this temporal and spatial specificity in mice, we generated conditional KIAA1549:BRAF strains that coexpresses green fluorescent protein (GFP). Although both primary astrocytes and neural stem cells (NSCs) from these mice express f-BRAF and GFP as well as exhibit increased MEK activity, only f-BRAF-expressing NSCs exhibit increased proliferation in vitro. Using Cre driver lines in which KIAA1549:BRAF expression was directed to NSCs (f-BRAF; BLBP-Cre mice), astrocytes (f-BRAF; GFAP-Cre mice), and NG2 progenitor cells (f-BRAF; NG2-Cre mice), increased glial cell numbers were observed only in the cerebellum of f-BRAF; BLBP-Cre mice in vivo. The availability of this unique KIAA1549:BRAF conditional transgenic mouse strain will enable future mechanistic studies aimed at defining the developmentally-regulated temporal and spatial determinants that underlie low-grade astrocytoma formation in children.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Aparna
authors.initials: A
authors.lastname: Kaul
authors.forename: Yi-Hsien
authors.initials: YH
authors.lastname: Chen
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Emnett
authors.forename: Scott M
authors.initials: SM
authors.lastname: Gianino
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology; D001254:Astrocytoma / Q000235:genetics / Q000473:pathology; D001921:Brain / Q000378:metabolism; D049109:Cell Proliferation; D002531:Cerebellum / Q000166:cytology; D002648:Child; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D023421:Models, Animal; D058953:Neural Stem Cells / Q000502:physiology*; D009457:Neuroglia / Q000166:cytology / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D009928:Organ Specificity; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism*
chemical_list: D015514:Oncogene Proteins, Fusion; D049452:Green Fluorescent Proteins; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases
keywords: astrocyte; brain tumor; genetically-engineered mice; glioma; neural stem cell; pilocytic astrocytoma
references.citation: Cancer Res. 2008 Nov 1;68(21):8673-7
references.pmid: 18974108
references.citation: Brain. 2003 Jan;126(Pt 1):152-60
references.pmid: 12477702
references.citation: Childs Nerv Syst. 2001 Sep;17(9):503-11
references.pmid: 11585322
references.citation: J Pathol. 2009 Jun;218(2):172-81
references.pmid: 19373855
references.citation: J Clin Invest. 2011 Apr;121(4):1344-8
references.pmid: 21403401
references.citation: Nature. 2009 Jan 29;457(7229):603-7
references.pmid: 19092805
references.citation: J Neurosci. 2007 Nov 14;27(46):12623-9
references.pmid: 18003841
references.citation: Cell Stem Cell. 2007 Oct 11;1(4):443-57
references.pmid: 18371380
references.citation: Development. 2008 Jan;135(1):145-57
references.pmid: 18045844
references.citation: Neuropathol Appl Neurobiol. 2000 Aug;26(4):361-7
references.pmid: 10931370
references.citation: Mol Cell Biol. 2002 Jul;22(14):5100-13
references.pmid: 12077339
references.citation: J Neuropathol Exp Neurol. 2008 Sep;67(9):878-87
references.pmid: 18716556
references.citation: Diabetes. 2004 Apr;53(4):1030-7
references.pmid: 15047618
references.citation: Neurology. 2009 Nov 10;73(19):1526-31
references.pmid: 19794125
references.citation: Genes Dev. 2012 Dec 1;26(23):2561-6
references.pmid: 23152448
references.citation: Br J Cancer. 2009 Aug 18;101(4):722-33
references.pmid: 19603027
references.citation: Cancer Cell. 2012 Jul 10;22(1):131-8
references.pmid: 22789544
references.citation: Biotechniques. 2000 Jul;29(1):52, 54
references.pmid: 10907076
references.citation: Oncogene. 2010 Jan 21;29(3):335-44
references.pmid: 19855433
references.citation: J Pediatr. 1989 May;114(5):788-92
references.pmid: 2497236
references.citation: Glia. 2009 Aug 15;57(11):1239-49
references.pmid: 19191334
references.citation: Cancer Res. 2005 Apr 1;65(7):2755-60
references.pmid: 15805275
references.citation: Clin Cancer Res. 2011 Jun 1;17(11):3590-9
references.pmid: 21636552
references.citation: Oncogene. 2014 Jan 16;33(3):289-99
references.pmid: 23318450
references.citation: Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):15996-6001
references.pmid: 21896734
references.citation: Arch Ophthalmol. 1980 Mar;98(3):505-11
references.pmid: 6767467
references.citation: Genes Dev. 2010 Oct 15;24(20):2317-29
references.pmid: 20876733
references.citation: J Neuropathol Exp Neurol. 2012 Jan;71(1):66-72
references.pmid: 22157620
references.citation: J Neurosci. 2005 Jun 8;25(23):5584-94
references.pmid: 15944386