Pax6 exerts regional control of cortical progenitor proliferation via direct repression of Cdk6 and hypophosphorylation of pRb.
Pax6 exerts regional control of cortical progenitor proliferation via direct repression of Cdk6 and hypophosphorylation of pRb.
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DOI：
10.1016/j.neuron.2013.02.012
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发表时间：
2013-04-24
期刊：
影响因子：
16.2
通讯作者：
Price DJ
中科院分区：
文献类型：
--
作者：
Mi D;Carr CB;Georgala PA;Huang YT;Manuel MN;Jeanes E;Niisato E;Sansom SN;Livesey FJ;Theil T;Hasenpusch-Theil K;Simpson TI;Mason JO;Price DJ
Pax6 等转录因子的早期时空表达模式以区域特异性方式调节皮质祖细胞的机制尚不清楚。 Pax6 在发育中的皮质中呈梯度表达，对于正常的皮质生成至关重要。我们发现 Pax6 的组成性或条件性缺失会增加皮质祖细胞增殖，其数量随正常 Pax6 水平的区域变化而变化。我们比较了从 Pax6+/+ 和 Pax6−/− 皮质分离的同等 Pax6 表达祖细胞的基因表达谱，并鉴定了许多负调控的细胞周期基因，包括 Cyclins 和 Cdks。生化检测表明 Pax6 直接抑制 Cdk6 表达。细胞周期蛋白/Cdk 抑制会抑制视网膜母细胞瘤蛋白 (pRb) 磷酸化，从而限制直接促进细胞周期机制的基因的转录，我们发现 Pax6 会抑制 pRb 磷酸化并抑制参与 DNA 复制的基因。我们的结果表明 Pax6 对皮质祖细胞周期的调节是区域性的和直接的。 Pax6 缺失会增加区域特异性数量的皮质祖细胞增殖 这种效应的大小与正常 Pax6 表达水平直接相关 许多关键细胞周期调节因子的表达在 Pax6 缺失时增加 Pax6 直接抑制 Cdk6 表达并控制 pRb 磷酸化 转录因子 Pax6 调节前脑发育的多个方面。米等人。表明它对皮质细胞增殖发挥区域控制作用。它抑制细胞周期基因表达，直接抑制 Cdk6，并限制 pRb-E2F 途径的活性。
The mechanisms by which early spatiotemporal expression patterns of transcription factors such as Pax6 regulate cortical progenitors in a region-specific manner are poorly understood. Pax6 is expressed in a gradient across the developing cortex and is essential for normal corticogenesis. We found that constitutive or conditional loss of Pax6 increases cortical progenitor proliferation by amounts that vary regionally with normal Pax6 levels. We compared the gene expression profiles of equivalent Pax6-expressing progenitors isolated from Pax6+/+ and Pax6−/− cortices and identified many negatively regulated cell-cycle genes, including Cyclins and Cdks. Biochemical assays indicated that Pax6 directly represses Cdk6 expression. Cyclin/Cdk repression inhibits retinoblastoma protein (pRb) phosphorylation, thereby limiting the transcription of genes that directly promote the mechanics of the cell cycle, and we found that Pax6 inhibits pRb phosphorylation and represses genes involved in DNA replication. Our results indicate that Pax6’s modulation of cortical progenitor cell cycles is regional and direct. Pax6 loss increases cortical progenitor proliferation by region-specific amounts The size of this effect correlates directly with normal Pax6 expression levels Expression of many key cell-cycle regulators is increased in the absence of Pax6 Pax6 directly represses Cdk6 expression and controls pRb phosphorylation The transcription factor Pax6 regulates multiple aspects of forebrain development. Mi et al. show that it exerts regional control of cortical cell proliferation. It inhibits cell-cycle gene expression, directly repressing Cdk6, and limits the activity of the pRb-E2F pathway.
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影响因子：
64.8
作者：
HILL, RE;FAVOR, J;VANHEYNINGEN, V
通讯作者：
VANHEYNINGEN, V
影响因子：
6.4
作者：
Appolloni, Irene;Calzolari, Filippo;Malatesta, Paolo
通讯作者：
Malatesta, Paolo
影响因子：
11.4
作者：
Carr, A;Biggin, MD
通讯作者：
Biggin, MD
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
11.4
作者：
Kitagawa, M;Higashi, H;Taya, Y
通讯作者：
Taya, Y