Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors
Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors
复制标题
DOI：
10.1242/dev.00182
复制
发表时间：
2003-01-01
期刊：
影响因子：
4.6
通讯作者：
Rowitch, DH
中科院分区：
文献类型：
--
作者：
Kenney, AM;Cole, MD;Rowitch, DH
Hedgehog通路激活是发育过程中特定神经元前体细胞群扩增所必需的，并且是人类小脑肿瘤髓母细胞瘤的病因。我们报告，音刺猬（Shh）信号上调表达的原癌基因Nmyc在培养的小脑颗粒神经元前体（CGNP）的情况下，新的蛋白质合成。Nmyc的时空表达模式，而不是其他Myc家族成员，正好与发育中的小脑中的刺猬增殖活性区域相一致，并在Patched（Ptch）杂合子小鼠的髓母细胞瘤中观察到。Nmyc的过表达促进细胞自主性G（1）细胞周期蛋白上调和CGNP增殖，而不依赖于Shh信号传导。此外，体外Myc拮抗作用显著降低了Shh在培养的CGNP中的增殖作用。总之，这些发现确定Nmyc作为Shh通路的直接靶点，其功能是调节小脑颗粒神经元前体细胞的细胞周期进程。
Hedgehog pathway activation is required for expansion of specific neuronal precursor populations during development and is etiologic in the human cerebellar tumor, medulloblastoma. We report that sonic hedgehog (Shh) signaling upregulates expression of the protooncogene Nmyc in cultured cerebellar granule neuron precursors (CGNPs) in the absence of new protein synthesis. The temporal-spatial expression pattern of Nmyc, but not other Myc family members, precisely coincides with regions of hedgehog proliferative activity in the developing cerebellum and is observed in medulloblastomas of Patched (Ptch) heterozygous mice. Overexpression of Nmyc promotes cell-autonomous G(1) cyclin upregulation and CGNP proliferation independent of Shh signaling. Furthermore, Myc antagonism in vitro significantly decreases proliferative effects of Shh in cultured CGNPs. Together, these findings identify Nmyc as a direct target of the Shh pathway that functions to regulate cell cycle progression in cerebellar granule neuron precursors.