Microphthalmia due to p53-mediated apoptosis of anterior lens epithelial cells in mice lacking the CREB-2 transcription factor
Microphthalmia due to p53-mediated apoptosis of anterior lens epithelial cells in mice lacking the CREB-2 transcription factor
复制标题
DOI：
10.1006/dbio.2000.9699
复制
发表时间：
2000-06-01
影响因子：
2.7
通讯作者：
Leiden, TM
中科院分区：
文献类型：
--
作者：
Hettmann, T;Barton, K;Leiden, TM
CREB-2（也称为ATF4、TAXREB67或C/ATF）是碱性亮氨酸拉链转录因子CREB/ATF家族中进化保守的成员。CREB-2在成年小鼠中普遍表达，可以作为转录激活因子和转录抑制因子。然而，人们对CREB-2在哺乳动物发育或器官生理中的正常功能知之甚少。在本报告中，我们使用基因靶向产生CREB-2缺陷（CREB-2(-/-)）小鼠。成年CREB-2（-/-）小鼠由于晶状体完全缺失而表现出小眼症。这些小鼠的早期胚胎晶状体发育包括视神经囊泡的形成、初级晶状体纤维和前上皮细胞的增殖。然而，从ED 14.5开始，缺乏creb -2的前上皮晶状体细胞发生大量同步凋亡。随后发育中的晶状体被完全吸收。与这种前上皮细胞存活缺陷相一致，原位杂交研究表明，CREB-2在ED 14.5的野生型前上皮晶状体细胞中高水平表达。CREB-2（-/-）小鼠的晶状体形成缺陷与Pax-6、α - a -晶体蛋白、c-maf或PDGF-R α表达的定性缺陷无关。然而，前上皮细胞的凋亡是由p53依赖的细胞死亡途径介导的，因为p53基因的消融挽救了前上皮细胞的死亡，并允许在缺乏CREB-2的情况下形成晶状体。综上所述，这些结果确定CREB-2是哺乳动物晶状体发育的重要调节因子。(C) 2000年学术出版社。
CREB-2 (also called ATF4, TAXREB67, or C/ATF) is an evolutionarily conserved member of the CREB/ATF family of basic-leucine zipper transcription factors. CREB-2 is expressed ubiquitously in the adult mouse and can function as both a transcriptional activator and a repressor. However, little was understood about the normal function of CREB-2 in mammalian development or organ physiology. In this report we have used gene targeting to produce CREB-2-deficient (CREB-2(-/-)) mice. Adult CREB-2(-/-) mice displayed microphthalmia due to the complete absence of a lens. Early embryonic lens development including formation of the optic vesicle, primary lens fibers, and proliferating anterior epithelial cells occurred normally in these mice. However, beginning at ED 14.5 the CREB-2-deficient anterior epithelial lens cells underwent massive and synchronous apoptosis. This was followed by the complete resorption of the developing lens. Consistent with this defect in anterior epithelial cell survival, in situ hybridization studies showed that CREB-2 is expressed at high levels in wild-type anterior epithelial lens cells at ED 14.5. The defect in lens formation seen in the CREB-2(-/-) mice was not associated with qualitative defects in the expression of Pax-6, alpha A-crystallin, c-maf, or PDGF-R alpha. However, apoptosis of the anterior epithelial cells was mediated by a p53-dependent cell death pathway because ablation of the p53 gene rescued anterior epithelial cell death and allowed the formation of a lens in the absence of CREB-2. Taken together, these results identify CREB-2 as an important regulator of mammalian lens development. (C) 2000 Academic Press.