LKB1 Regulates Cerebellar Development by Controlling Sonic Hedgehog-mediated Granule Cell Precursor Proliferation and Granule Cell Migration.
LKB1 Regulates Cerebellar Development by Controlling Sonic Hedgehog-mediated Granule Cell Precursor Proliferation and Granule Cell Migration.
复制标题
LKB1 通过控制 Sonic Hedgehog 介导的颗粒细胞前体增殖和颗粒细胞迁移来调节小脑发育
DOI：
10.1038/srep16232
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发表时间：
2015-11-09
影响因子：
4.6
通讯作者：
Gao J
中科院分区：
文献类型：
--
作者：
Men Y;Zhang A;Li H;Jin Y;Sun X;Li H;Gao J
肝激酶B1（LKB 1）基因在细胞分化、增殖和细胞极性的建立中起着至关重要的作用。我们建立了LKB 1条件性基因敲除小鼠（LKB 1Atoh 1CKO），以研究LKB 1在小脑发育中的作用。LKB 1Atoh 1CKO小鼠表现出运动功能障碍。在LKB 1Atoh 1CKO小脑中，整体结构体积较大，小叶较多。LKB 1失活导致颗粒细胞前体细胞（GCPs）增殖增加，颗粒细胞迁移异常和单极刷状细胞过度产生。为了研究异常叶状的机制，我们研究了音刺猬信号（Shh）通过测试其转录介质，Gli蛋白，调节GCPs增殖和小脑发育过程中的小脑叶状。Gli基因在突变小脑中的表达水平显著增加，体外培养的突变小脑GCPs的增殖显著增加，而Shh抑制剂GDC-0049的存在显著降低了突变GCPs的增殖。因此，LKB 1Atoh 1CKO小鼠中的LKB 1缺陷增强了Shh信号传导，导致过度的GCP增殖和额外小叶的形成。我们提出LKB 1通过在小脑发育期间通过Shh信号传导控制GCPs增殖来调节小脑发育。
The Liver Kinase B1 (LKB1) gene plays crucial roles in cell differentiation, proliferation and the establishment of cell polarity. We created LKB1 conditional knockout mice (LKB1Atoh1CKO) to investigate the function of LKB1 in cerebellar development. The LKB1Atoh1CKO mice displayed motor dysfunction. In the LKB1Atoh1CKO cerebellum, the overall structure had a larger volume and morelobules. LKB1 inactivationled to an increased proliferation of granule cell precursors (GCPs), aberrant granule cell migration and overproduction of unipolar brush cells. To investigate the mechanism underlying the abnormal foliation, we examined sonic hedgehog signalling (Shh) by testing its transcriptional mediators, the Gli proteins, which regulate the GCPs proliferation and cerebellar foliation during cerebellar development. The expression levels of Gli genes were significantly increased in the mutant cerebellum.In vitroassays showed that the proliferation of cultured GCPs from mutant cerebellum significantly increased, whereas the proliferation of mutant GCPs significantly decreased in the presence of a Shh inhibitor GDC-0049. Thus, LKB1 deficiency in the LKB1Atoh1CKO mice enhanced Shh signalling, leading to the excessive GCP proliferation and the formation of extra lobules. We proposed that LKB1 regulates cerebellar development by controlling GCPs proliferation through Shh signalling during cerebellar development.