Kaul Aparna, Chen Yi-Hsien, Emnett Ryan J, Gianino Scott M, Gutmann David H
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri.
Genesis. 2013 Oct;51(10):708-16. doi: 10.1002/dvg.22415. Epub 2013 Aug 16.
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.
低级别脑肿瘤（毛细胞型星形细胞瘤）由基因组重排导致，其中BRAF激酶结构域与KIAA1549基因的氨基末端融合（KIAA1549:BRAF融合；f-BRAF），常见于幼儿的小脑。为了在小鼠中模拟这种时间和空间特异性，我们构建了共表达绿色荧光蛋白（GFP）的条件性KIAA1549:BRAF品系。尽管来自这些小鼠的原代星形胶质细胞和神经干细胞（NSC）均表达f-BRAF和GFP，且MEK活性增强，但只有表达f-BRAF的NSC在体外表现出增殖增加。利用Cre驱动系，使KIAA1549:BRAF表达定向于NSC（f-BRAF；BLBP-Cre小鼠）、星形胶质细胞（f-BRAF；GFAP-Cre小鼠）和NG2祖细胞（f-BRAF；NG2-Cre小鼠），在体内仅在f-BRAF；BLBP-Cre小鼠的小脑中观察到胶质细胞数量增加。这种独特的KIAA1549:BRAF条件性转基因小鼠品系的可得性将有助于未来开展机制研究，旨在确定儿童低级别星形细胞瘤形成背后的发育调控时间和空间决定因素。
