Fbxl10/Kdm2b deficiency accelerates neural progenitor cell death and leads to exencephaly
Fbxl10/Kdm2b deficiency accelerates neural progenitor cell death and leads to exencephaly
复制标题
DOI：
10.1016/j.mcn.2011.01.001
复制
发表时间：
2011-03-01
影响因子：
3.5
通讯作者：
Yoshida, Nobuaki
中科院分区：
文献类型：
--
作者：
Fukuda, Tsuyoshi;Tokunaga, Akinori;Yoshida, Nobuaki
组蛋白甲基化是影响哺乳动物发育和细胞分化的重要转录调控系统。表观遗传基因调控的改变与疾病有关。Fbxl10 （F-box和富含亮氨酸的重复蛋白10）是一种含有JmjC结构域的组蛋白去甲基化酶。尽管Fbxl10参与细胞周期调节、细胞死亡、衰老和肿瘤发生，但这些功能存在争议，其生理功能尚不清楚。为了确定Fbxl10在体内的功能，在本研究中，我们对小鼠Fbxl10基因进行了纯合突变。大约一半的fbx110缺陷小鼠表现出神经管关闭失败，导致畸形，出生后不久死亡。Fbxl10缺乏也会导致视网膜缺损和低外显率的卷曲尾。Fbxl10 mRNA在E8.5胚胎的颅神经褶皱中特异性表达，Fbxl10缺陷E9.5胚胎的神经上皮和间质细胞凋亡增加，与Fbxl10缺陷小鼠的神经管缺陷一致。Fbxl10的缺失导致E8.5胚胎和小鼠胚胎成纤维细胞中凋亡诱导剂p19ARF的表达增加。此外，突变体E14.5脑中有丝分裂神经祖细胞的数量显著增加。我们的研究结果表明，Fbxl10基因通过调节小鼠细胞增殖和细胞死亡，对胚胎神经发育起重要作用。(C) 2011爱思唯尔公司版权所有。
Histone methylation is the important transcription regulatory system that affects mammalian development and cell differentiation. Alterations in epigenetic gene regulation are associated with disease. Fbxl10 (F-box and leucine-rich repeat protein 10) is a JmjC domain-containing histone demethylase. Although Fbxl10 has been implicated in cell cycle regulation, cell death, senescence, and tumorigenesis, these functions are controversial and its physiological function is unclear. To determine the in vivo function of Fbxl10, in this study, we generated a homozygous mutation in the mouse Fbxl10 gene. About half of Fbxl10-deficient mice exhibit failure of neural tube closure, resulting in exencephaly and die shortly after birth. Fbxl10 deficiency also causes retinal coloboma and a curled tail with low penetrances. Fbxl10 mRNA is specifically expressed in the cranial neural folds at E8.5 embryos, and apoptosis increased in the neuroepithelium and mesenchyme of Fbxl10-deficient E9.5 embryos, consistent with neural tube defects found in Fbxl10-deficient mice. Depletion of Fbxl10 induced the increased expression of p19ARF, an inducer of apoptosis, in E8.5 embryos and mouse embryonic fibroblast cells. In addition, the number of mitotic neural progenitor cells is significantly increased in the mutant E14.5 brain. Our findings suggest that the Fbxl10 gene makes important contributions to embryonic neural development by regulating cell proliferation and cell death in mice. (C) 2011 Elsevier Inc. All rights reserved.