A role for p27/Kip1 in the control of cerebellar granule cell precursor proliferation

被引:132
作者
Miyazawa, K
Himi, T
Garcia, V
Yamagishi, H
Sato, S
Ishizaki, Y
机构
[1] Kobe Univ, Sch Med, Dept Hyg, Chuo Ku, Kobe, Hyogo 6500017, Japan
[2] Kyoto Prefectural Univ Med, Dept Surg, Kamigyo Ku, Kyoto 6020841, Japan
[3] Tokyo Med & Dent Univ, Postgrad Sch, Dept Physiol Chem, Bunkyo Ku, Tokyo 1138549, Japan
关键词
cyclin-dependent kinase inhibitor; p27; cerebellum; cerebellar granule cells; proliferation; cell cycle;
D O I
10.1523/JNEUROSCI.20-15-05756.2000
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
During development, control of proliferation of neuronal precursor cells plays a crucial role in determining the number of neurons. Proliferation is driven by mitogens, but how it is terminated remains a mystery. In this study, we examined the role of cyclin-dependent kinase inhibitors in the control of proliferation of cerebellar granule cell precursors (GCPs). Among the inhibitors we examined, only p27/Kip1 (p27) was expressed at significant levels in cells of the granule cell lineage in the developing and adult cerebellum. In developing cerebella, p27 was expressed in the external germinal layer (the deeper regions), the molecular layer, and the granule layer. In adult cerebella, p27 was expressed in the cells of the granule layer. We isolated and purified GCPs from cerebella of developing mice and examined their bromodeoxyuridine (BrdU) uptake and p27 expression at various times. We found that there was an inverse correlation between BrdU uptake and p27 expression. Even in the presence of saturating amounts of Sonic hedgehog, a potent mitogen, the cells eventually stopped dividing and differentiated, expressing p27 strongly. We also examined mice in which one or both copies of the p27 gene have been inactivated by targeted gene disruption and found that their cerebella were larger than those of wild-type mice. In cell cultures, GCPs prepared from p27-deficient mice showed enhanced proliferation compared with GCPs from wildtype mice. Taken together, these results suggest that there is an intracellular mechanism that stops GCP division and causes GCPs to differentiate and that p27 is part of this mechanism.
引用
收藏
页码:5756 / 5763
页数:8
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