Distinct Developmental Roles of Cell Cycle Inhibitors p57Kip2 and p27Kip1 Distinguish Pituitary Progenitor Cell Cycle Exit from Cell Cycle Reentry of Differentiated Cells
Distinct Developmental Roles of Cell Cycle Inhibitors p57Kip2 and p27Kip1 Distinguish Pituitary Progenitor Cell Cycle Exit from Cell Cycle Reentry of Differentiated Cells
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DOI：
10.1128/mcb.01885-08
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发表时间：
2009-04-01
影响因子：
5.3
通讯作者：
Drouin, Jacques
中科院分区：
文献类型：
--
作者：
Bilodeau, Steve;Roussel-Gervais, Audrey;Drouin, Jacques
通常认为模式和分化信号驱动发育程序，包括增殖祖细胞的细胞周期退出。利用发育中的垂体前叶内增殖和分化细胞的空间和时间分离，我们研究了器官发生过程中细胞增殖的控制。因此，我们确定了一个人口的非循环前体，是唯一的标志表达的细胞周期抑制剂p57（Kip 2）和细胞周期蛋白E。在p57（Kip 2-/-）小鼠中，由于增殖祖细胞的积累，发育中的垂体是增生的，而p57（Kip 2）的过表达导致发育不全。分化不需要p57（Kip 2）依赖性细胞周期退出，相反，如在Tpit（-/-）垂体中实现的细胞分化的阻断不会阻止细胞周期退出，而是导致p57（Kip 2）阳性前体的积累。分化后，p57（Kip 2）被p27（Kip 1）取代。因此，在p27（Kip 1-/-）垂体中容易检测到增殖分化细胞，但在野生型或p57（Kip 2-/-）垂体中不容易检测到。值得注意的是，所有p57（Kip 2-/-）和p27（Kip 1-/-）垂体细胞都是增殖性的。因此，在正常发育过程中，祖细胞周期的退出是由p57（Kip 2），其次是p27（Kip 1）在分化的细胞控制;这些顺序的行动，连同不同的垂体功能丧失的结果，建议分层控制的细胞周期是独立的分化。
Patterning and differentiation signals are often believed to drive the developmental program, including cell cycle exit of proliferating progenitors. Taking advantage of the spatial and temporal separation of proliferating and differentiated cells within the developing anterior pituitary gland, we investigated the control of cell proliferation during organogenesis. Thus, we identified a population of noncycling precursors that are uniquely marked by expression of the cell cycle inhibitor p57(Kip2) and by cyclin E. In p57(Kip2-/-) mice, the developing pituitary is hyperplastic due to accumulation of proliferating progenitors, whereas overexpression of p57(Kip2) leads to hypoplasia. p57(Kip2)-dependent cell cycle exit is not required for differentiation, and conversely, blockade of cell differentiation, as achieved in Tpit(-/-) pituitaries, does not prevent cell cycle exit but rather leads to accumulation of p57(Kip2)-positive precursors. Upon differentiation, p57(Kip2) is replaced by p27(Kip1). Accordingly, proliferating differentiated cells are readily detected in p27(Kip1-/-) pituitaries but not in wild-type or p57(Kip2-/-) pituitaries. Strikingly, all cells of p57(Kip2-/-); p27(Kip1-/-) pituitaries are proliferative. Thus, during normal development, progenitor cell cycle exit is controlled by p57(Kip2) followed by p27(Kip1) in differentiated cells; these sequential actions, taken together with different pituitary outcomes of their loss of function, suggest hierarchical controls of the cell cycle that are independent of differentiation.