Cyclin D1 fine-tunes the neurogenic output of embryonic retinal progenitor cells.
Cyclin D1 fine-tunes the neurogenic output of embryonic retinal progenitor cells.
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DOI：
10.1186/1749-8104-4-15
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发表时间：
2009-05-05
影响因子：
3.6
通讯作者：
Levine EM
中科院分区：
文献类型：
--
作者：
Das G;Choi Y;Sicinski P;Levine EM
维持视网膜祖细胞（RPC）增殖与分化的正确平衡对于视网膜的正常发育至关重要。细胞周期调节因子细胞周期蛋白D1在RPC中表达，在细胞周期蛋白D1基因座（Ccnd 1-/-）具有靶向无效等位基因的小鼠具有小眼症和细胞减少性视网膜，后一种表型归因于出生后RPC增殖减少和感光细胞死亡增加。细胞周期蛋白D1如何影响RPC行为，特别是在胚胎期，目前尚不清楚。在这项研究中，我们表明，胚胎RPC缺乏细胞周期蛋白D1的进展，通过细胞周期以较慢的速度和退出细胞周期以较快的速度。与增强的细胞周期退出一致，在胚胎期出生的细胞类型的相对比例增加，例如视网膜神经节细胞和感光细胞。出乎意料的是，细胞周期蛋白D1缺乏会降低其他早期出生的视网膜神经元的比例，即水平细胞和特定的无长突细胞类型。我们还发现，水平细胞和其他细胞类型的层状定位在细胞周期蛋白D1的情况下改变。用细胞周期蛋白D2取代细胞周期蛋白D1在纠正由于细胞周期蛋白D1缺陷引起的表型方面是无效的，这表明D-细胞周期蛋白不是完全冗余的。替换细胞周期蛋白E或细胞周期蛋白依赖性激酶抑制剂p27 Kip 1的失活恢复平衡的RPC和视网膜细胞类型更正常的分布，这表明视网膜母细胞瘤途径的调节是一个重要的功能，细胞周期蛋白D1在胚胎视网膜发育。我们的研究结果表明，细胞周期蛋白D1在RPC细胞周期调控和视网膜组织发生中具有重要作用。RPC人口减少，由于较长的细胞周期时间和细胞周期退出的增强率可能是主要因素驱动视网膜hypocellularity和改变输出的前体群体在胚胎Ccnd 1-/-视网膜。
Maintaining the correct balance of proliferation versus differentiation in retinal progenitor cells (RPCs) is essential for proper development of the retina. The cell cycle regulator cyclin D1 is expressed in RPCs, and mice with a targeted null allele at the cyclin D1 locus (Ccnd1-/-) have microphthalmia and hypocellular retinas, the latter phenotype attributed to reduced RPC proliferation and increased photoreceptor cell death during the postnatal period. How cyclin D1 influences RPC behavior, especially during the embryonic period, is unclear. In this study, we show that embryonic RPCs lacking cyclin D1 progress through the cell cycle at a slower rate and exit the cell cycle at a faster rate. Consistent with enhanced cell cycle exit, the relative proportions of cell types born in the embryonic period, such as retinal ganglion cells and photoreceptor cells, are increased. Unexpectedly, cyclin D1 deficiency decreases the proportions of other early born retinal neurons, namely horizontal cells and specific amacrine cell types. We also found that the laminar positioning of horizontal cells and other cell types is altered in the absence of cyclin D1. Genetically replacing cyclin D1 with cyclin D2 is not efficient at correcting the phenotypes due to the cyclin D1 deficiency, which suggests the D-cyclins are not fully redundant. Replacement with cyclin E or inactivation of cyclin-dependent kinase inhibitor p27Kip1 restores the balance of RPCs and retinal cell types to more normal distributions, which suggests that regulation of the retinoblastoma pathway is an important function for cyclin D1 during embryonic retinal development. Our findings show that cyclin D1 has important roles in RPC cell cycle regulation and retinal histogenesis. The reduction in the RPC population due to a longer cell cycle time and to an enhanced rate of cell cycle exit are likely to be the primary factors driving retinal hypocellularity and altered output of precursor populations in the embryonic Ccnd1-/- retina.
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影响因子：
56.9
作者：
DENOOIJ, JC;HARIHARAN, IK
通讯作者：
HARIHARAN, IK
影响因子：
64.5
作者：
deNooij, JC;Letendre, MA;Hariharan, IK
通讯作者：
Hariharan, IK
DOI：
10.1073/pnas.89.4.1194
发表时间：
1992-02-15
影响因子：
11.1
作者：
ALUBAIDI, MR;HOLLYFIELD, JG;BAEHR, W
通讯作者：
BAEHR, W
影响因子：
5.3
作者：
Baye, Lisa M.;Link, Brian A.
通讯作者：
Link, Brian A.
影响因子：
5.4
作者：
Donovan, Stacy L.;Schweers, Brett;Dyer, Michael A.
通讯作者：
Dyer, Michael A.