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Zfp423 Is Required for Normal Cerebellar Development

机译：Zfp423是正常小脑发育所必需的

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Zinc finger protein 423 (also known as Ebf-associated zinc finger protein, Ebfaz) binds to and negatively regulates Ebf1, a basic helix-loop-helix transcription factor required for B-cell lineage commitment and olfactory epithelium development. Zfp423 also binds to Smad1/Smad4 in response to Bmp2 signaling. Zfp423 contains 30 Krüppel-like zinc fingers that are organized into discrete clusters; some zinc fingers are used to bind DNA, while others mediate Zfp423's interaction with other signaling proteins such as Ebf1 and Smad1/Smad4. Previously, we showed that Zfp423 is an oncogene whose upregulation following retroviral integration in murine B cells leads to an arrest in B-cell differentiation and the subsequent development of B-cell lymphomas. To study the biological functions of Zfp423 in vivo, we used recombineering and gene targeting to generate mice that carry conditional as well as null alleles of Zfp423. Homozygous Zfp423 null mice are runted and ataxic, the cerebellum is underdeveloped, and the vermis is severely reduced. In the remaining cerebellar structures, the Purkinje cells are poorly developed and mislocalized. In mice carrying a hypomorphic Zfp423 gene trap allele, lacZ expression in the cerebellum correlates with the Purkinje cell layer, suggesting that these phenotypes are a result of a Purkinje cell-intrinsic defect.
机译：锌指蛋白423（也称为Ebf相关锌指蛋白，Ebfaz）与Ebf1结合并对其负调控，Ebf1是B细胞谱系定型和嗅觉上皮形成所必需的基本螺旋-环-螺旋转录因子。 Zfp423还响应Bmp2信号传导与Smad1 / Smad4结合。 Zfp423包含30个类似于Krüppel的锌指，这些锌指被组织成离散的簇。一些锌指用于结合DNA，而另一些锌指介导Zfp423与其他信号蛋白（例如Ebf1和Smad1 / Smad4）的相互作用。先前，我们显示 Zfp423 是一种癌基因，在鼠B细胞中逆转录病毒整合后其上调导致B细胞分化停滞并随后发生B细胞淋巴瘤。为了研究 Zfp423 在体内的生物学功能，我们使用了重组和基因靶向技术来生成携带 Zfp423 的条件等位基因和无效等位基因的小鼠。纯合子 Zfp423 缺失小鼠，失神，小脑发育不足，,骨严重缩小。在其余的小脑结构中，浦肯野细胞发育不良且定位错误。在携带亚型 Zfp423 基因陷阱等位基因的小鼠中，小脑中的 lacZ 表达与浦肯野细胞层相关，表明这些表型是浦肯野细胞固有缺陷的结果。

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