Transposon mutagenesis with coat color genotyping identifies an essential role for Skor2 in sonic hedgehog signaling and cerebellum development
Transposon mutagenesis with coat color genotyping identifies an essential role for Skor2 in sonic hedgehog signaling and cerebellum development
复制标题
DOI：
10.1242/dev.067264
复制
发表时间：
2011-10-15
期刊：
影响因子：
4.6
通讯作者：
Zheng, Hui
中科院分区：
文献类型：
--
作者：
Wang, Baiping;Harrison, Wilbur;Zheng, Hui
小脑的正确发育需要浦肯野细胞向颗粒细胞发出协调的音hedgehog （Shh）信号。在浦肯野细胞中，Shh的表达是如何被调节的，人们知之甚少。使用一种新的酪氨酸酶标记的睡美人转座子介导的突变，允许基于毛色的基因分型，我们创建了Ski/ snoo家族转录共抑制因子2 （Skor2）基因缺失的小鼠。Skor2的缺失导致浦肯野细胞发育缺陷，颗粒细胞增殖严重减少和小脑畸形。Skor2在大脑中的浦肯野细胞中特异性表达，这是Shh正确表达所必需的。Skor2过表达以hdac依赖的方式抑制BMP信号并刺激Shh启动子活性，提示Skor2通过抑制BMP信号激活Shh表达。我们的研究确定了Skor2作为浦肯野细胞中一种新的转录调节因子的基本功能，它在小脑发育过程中作用于Shh的上游。
Correct development of the cerebellum requires coordinated sonic hedgehog (Shh) signaling from Purkinje to granule cells. How Shh expression is regulated in Purkinje cells is poorly understood. Using a novel tyrosinase minigene-tagged Sleeping Beauty transposon-mediated mutagenesis, which allows for coat color-based genotyping, we created mice in which the Ski/Sno family transcriptional co-repressor 2 (Skor2) gene is deleted. Loss of Skor2 leads to defective Purkinje cell development, a severe reduction of granule cell proliferation and a malformed cerebellum. Skor2 is specifically expressed in Purkinje cells in the brain, where it is required for proper expression of Shh. Skor2 overexpression suppresses BMP signaling in an HDAC-dependent manner and stimulates Shh promoter activity, suggesting that Skor2 represses BMP signaling to activate Shh expression. Our study identifies an essential function for Skor2 as a novel transcriptional regulator in Purkinje cells that acts upstream of Shh during cerebellum development.