Lamar Elise, Kintner Chris
Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Development. 2005 Aug;132(16):3619-30. doi: 10.1242/dev.01937.
The HES family of bHLH repressors plays a key role in regulating the differentiation of neural precursors in the vertebrate embryo. Members of the HES gene family are expressed in neural precursors as targets of the Notch signaling pathway, but how this occurs in the context of neurogenesis is not known. Here, we address this issue by identifying enhancers driving Notch-dependent gene expression of two Hes5-like genes expressed in Xenopus called Esr1 and Esr10. Using frog transgenesis, we identify enhancer elements driving expression of Esr1 and Esr10 in neural precursors or in response to ectopic expression of the proneural protein, Xngnr1. Using deletion and mutation analysis, we define motifs required for enhancer activity of both genes, namely Notch-responsive elements and, in the case of Esr10, E-box motifs. We find that Esr1 and Esr10 are differentially regulated both in terms of Notch input and its interaction with heterologous factors. These studies reveal inputs required for proneural expression of genes encoding bHLH repressors in the developing vertebrate nervous system.
bHLH 抑制因子的 HES 家族在调节脊椎动物胚胎神经前体细胞的分化过程中起着关键作用。HES 基因家族的成员在神经前体细胞中作为 Notch 信号通路的靶点表达，但在神经发生的背景下这一过程如何发生尚不清楚。在此，我们通过鉴定驱动非洲爪蟾中两个名为 Esr1 和 Esr10 的 Hes5 样基因的 Notch 依赖性基因表达的增强子来解决这个问题。利用青蛙转基因技术，我们鉴定出在神经前体细胞中或响应神经前体蛋白 Xngnr1 的异位表达而驱动 Esr1 和 Esr10 表达的增强子元件。通过缺失和突变分析，我们确定了这两个基因增强子活性所需的基序，即 Notch 反应元件，对于 Esr10 而言，还有 E-box 基序。我们发现 Esr1 和 Esr10 在 Notch 输入及其与异源因子的相互作用方面受到不同的调控。这些研究揭示了发育中的脊椎动物神经系统中编码 bHLH 抑制因子的基因神经前体表达所需的输入。
