Dual control of Neurogenesis by PC3 through cell cycle inhibition and induction of Math1
Dual control of Neurogenesis by PC3 through cell cycle inhibition and induction of Math1
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DOI：
10.1523/jneurosci.3860-03.2004
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发表时间：
2004-03-31
影响因子：
5.3
通讯作者：
Tirone, F
中科院分区：
文献类型：
--
作者：
Canzoniere, D;Farioli-Vecchioli, S;Tirone, F
越来越多的证据表明，细胞周期阻滞和神经发生是高度协调和相互作用的过程，由细胞周期基因和神经转录因子控制。基因PC 3（Tis 21/BTG 2）在整个神经管的成神经细胞中表达，并通过抑制细胞周期蛋白D1的转录在G（1）检查点抑制细胞周期进程。我们产生了诱导型小鼠模型，其中PC 3的表达在神经管和小脑的神经元前体中上调。这些小鼠表现出显着增加有丝分裂后神经元的生产和小脑发育障碍。PC 3转基因小鼠的小脑颗粒前体细胞周期蛋白D1表达的抑制和Math 1，其分化所需的转录因子的表达的强烈增加。此外，由重组腺病毒编码的PC 3也在体外诱导有丝分裂后颗粒细胞中的Math 1，并刺激Math 1启动子活性。相比之下，PC 3的表达在Math 1基因敲除小鼠的小脑原基中不受影响，这表明PC 3在Math 1的上游起作用。作为一个整体，我们的数据表明，细胞周期退出小脑颗粒细胞前体细胞和小脑神经发生的发生是协调PC 3通过转录控制细胞周期蛋白D1和数学1，分别。
Growing evidence indicates that cell cycle arrest and neurogenesis are highly coordinated and interactive processes, governed by cell cycle genes and neural transcription factors. The gene PC3 (Tis21/BTG2) is expressed in the neuroblast throughout the neural tube and inhibits cell cycle progression at the G(1) checkpoint by repressing cyclin D1 transcription. We generated inducible mouse models in which the expression of PC3 was upregulated in neuronal precursors of the neural tube and of the cerebellum. These mice exhibited a marked increase in the production of postmitotic neurons and impairment of cerebellar development. Cerebellar granule precursors of PC3 transgenic mice displayed inhibition of cyclin D1 expression and a strong increase in the expression of Math1, a transcription factor required for their differentiation. Furthermore, PC3, encoded by a recombinant adenovirus, also induced Math1 in postmitotic granule cells in vitro and stimulated the Math1 promoter activity. In contrast, PC3 expression was unaffected in the cerebellar primordium of Math1 null mice, suggesting that PC3 acts upstream to Math1. As a whole, our data suggest that cell cycle exit of cerebellar granule cell precursors and the onset of cerebellar neurogenesis are coordinated by PC3 through transcriptional control of cyclin D1 and Math1, respectively.