The F-box protein Fbw7 is required for cerebellar development
The F-box protein Fbw7 is required for cerebellar development
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DOI：
10.1016/j.ydbio.2011.07.030
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发表时间：
2011-10-01
影响因子：
2.7
通讯作者：
Behrens, Axel
中科院分区：
文献类型：
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作者：
Jandke, Anett;Da Costa, Clive;Behrens, Axel
F-box蛋白Fbw 7（也称为Fbxw 7、hCdc 4和Se 1 -10）作为SCF型E3泛素连接酶的底物识别组分发挥功能。SCF（Fbw 7）促进Notch、细胞周期蛋白E、c-Myc和c-Jun等多种蛋白质的多聚遍在蛋白质化和随后的降解。Fbw 7在神经系统中高度表达，并在胚胎发育期间通过Notch和c-Jun控制神经干细胞分化和细胞凋亡（Hoeck等人，2010年）。神经谱系中的Fbw 7缺失是围产期致死的，因此禁止研究Fbw 7在成人神经系统中的作用。fbw 7 mRNA在出生后的大脑中高度表达，为了深入了解Fbw 7在出生后神经发生中的功能，我们分析了Fbw 7在小脑中的功能。我们通过特异性地在小脑原基中失活Fbw 7来产生条件性Fbw 7敲除小鼠（fbw 7（Delta Cb））。这导致小脑体积减小，浦肯野细胞数量减少和轴突分支缺陷。此外，Fbw 7缺陷型小脑表现出髓上裂和异常的祖细胞迁移。Fbw 7底物Notch 1和N-末端磷酸化c-Jun的蛋白质水平在fbw 7（Delta Cb）小鼠中上调。伴随c-Jun的缺失，以及特异性消除c-Jun N-末端磷酸化的junAA敲入突变，挽救了浦肯野细胞数量和fbw 7（Delta Cb）背景中的树枝状结构。总之，这些数据表明，Fbw 7是必不可少的小脑发育过程中，并确定N-末端磷酸化的c-Jun作为一个重要的SCF（Fbw 7）在神经发生的底物。(C)2011 Elsevier Inc. All rights reserved.
The F-box protein Fbw7 (also known as Fbxw7, hCdc4 and Se1-10) functions as a substrate recognition component of a SCF-type E3 ubiquitin ligase. SCF(Fbw7) facilitates polyubiquitination and subsequent degradation of various proteins such as Notch, cyclin E, c-Myc and c-Jun. Fbw7 is highly expressed in the nervous system and controls neural stem cell differentiation and apoptosis via Notch and c-Jun during embryonic development (Hoeck et al., 2010). Fbw7 deletion in the neural lineage is perinatal lethal and thus prohibits studying the role of Fbw7 in the adult nervous system. fbw7 mRNA is highly expressed in the postnatal brain and to gain insights into the function of Fbw7 in postnatal neurogenesis we analysed Fbw7 function in the cerebellum. We generated conditional Fbw7-knockout mice (fbw7(Delta Cb)) by inactivating Fbw7 specifically in the cerebellar anlage. This resulted in decreased cerebellar size, reduced Purkinje cell number and defects in axonal arborisation. Moreover, Fbw7-deficient cerebella showed supranumeral fissures and aberrant progenitor cell migration. Protein levels of the Fbw7 substrates Notch1 and N-terminally phosphorylated c-Jun were upregulated in fbw7(Delta Cb) mice. Concomitant deletion of c-Jun, and also the junAA knock-in mutation which specifically abrogates c-Jun N-terminal phosphorylation, rescued Purkinje cell numbers and arborisation in the fbw7(Delta Cb) background. Taken together these data demonstrate that Fbw7 is essential during cerebellar development, and identify N-terminally phosphorylated c-Jun as an important substrate of SCF(Fbw7) during neurogenesis. (C) 2011 Elsevier Inc. All rights reserved.