Genetic rescue of Cdk4 null mice restores pancreatic β-cell proliferation but not homeostatic cell number
Genetic rescue of Cdk4 null mice restores pancreatic β-cell proliferation but not homeostatic cell number
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DOI：
10.1038/sj.onc.1206506
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发表时间：
2003-08-14
期刊：
影响因子：
8
通讯作者：
Barbacid, M
中科院分区：
文献类型：
--
作者：
Martín, J;Hunt, SL;Barbacid, M
小鼠缺乏CDK4表达会导致胰岛素缺乏性糖尿病和女性不育，这分别是由于胰岛β细胞和产生催乳素的脑下垂体促乳素细胞数量减少所致。CDK4基因缺失的小鼠也表现出身体和器官大小的减少。在这里，我们表明，CDK4对于胰岛β细胞的出生后增殖是必不可少的，但对导管上皮细胞的胚胎新生来说并不是必需的。内源性CDK4在CDK4基因缺失小鼠的β细胞和脑垂体中的重新表达可恢复细胞增殖，并导致生育和血糖正常的动物，从而表明这些细胞群体中的增殖缺陷是细胞自主的，因为缺乏CDK4的表达。然而，这些小鼠的体积仍然很小，这表明这种表型不是因为胰腺或脑垂体介导的内分泌缺陷。这种表型是细胞数量减少的结果，而不是细胞大小减少的结果。因此，哺乳动物的CDK4不仅参与控制特定细胞类型的增殖，而且可能在建立内稳态细胞数量方面发挥更广泛的作用。
Lack of Cdk4 expression in mice leads to insulin-deficient diabetes and female infertility owing to a reduced number of pancreatic beta cells and prolactin-producing pituitary lactotrophs, respectively. Cdk4 null mice display also reduced body and organ size. Here, we show that Cdk4 is essential for the postnatal proliferation of pancreatic beta cells but not for embryonic neogenesis from ductal epithelial cells. Re-expression of endogenous Cdk4 in beta cells and in the pituitary gland of Cdk4 null mice restores cell proliferation and results in fertile and normoglycemic animals, thus, demonstrating that the proliferation defects in these cellular populations are cell autonomous because of the lack of Cdk4 expression. However, these mice remain small in size, indicating that this phenotype is not because of pancreatic- or pituitary-mediated endocrine defects. This phenotype is a consequence of reduced cell numbers rather than reduced cell size. Thus, mammalian Cdk4 is not only involved in controlling proliferation of specific cell types but may play a wider role in establishing homeostatic cell numbers.