Mice lacking both presenilin genes exhibit early embryonic patterning defects
Mice lacking both presenilin genes exhibit early embryonic patterning defects
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DOI：
10.1101/gad.13.21.2801
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发表时间：
1999-11-01
影响因子：
10.5
通讯作者：
Bernstein, A
中科院分区：
文献类型：
--
作者：
Donoviel, DB;Hadjantonakis, AK;Bernstein, A
在蠕虫、苍蝇和人类中的遗传学研究表明，早老素参与了Notch信号通路的调节和阿尔茨海默病的发病机制。哺乳动物中有两个高度同源的早老素基因，早老素1(PS1)和早老素2(PS2)。在小鼠中，PS1的失活会导致发育缺陷，最终导致围产期死亡。为了测试PS1缺失小鼠的晚期致死率是否反映了早老素的遗传冗余，我们通过基因打靶产生了PS2缺失小鼠，随后产生了PS1/PS2双缺失小鼠。PS2定向零突变的纯合子小鼠没有表现出明显的缺陷；然而，在PS1零背景下丢失PS2会导致胚胎在第9.5天死亡。缺乏这两种早老素的胚胎，以及令人惊讶的是，那些在PS1缺失的背景上只携带一份PS2拷贝的胚胎，表现出多种早期图案缺陷，包括缺乏体节分割、躯干腹侧神经管解体、中脑间充质细胞丢失、前神经孔关闭延迟以及心脏和第二鳃弓发育异常。此外，位于Notch途径下游的两个基因Delta like-1(Dll1)和Hes-5在早老素双零胚胎中错误表达：Hes-5在这些小鼠中未检测到表达，而Dll1在双零胚胎的神经管和脑中异位表达。我们的结论是，早老素在胚胎发育中发挥着广泛的作用，PS1和PS2之间存在功能冗余，这两种脊椎动物的早老素和它们的无脊椎动物同源物一样，对于Notch信号是必不可少的。
Genetic studies in worms, flies, and humans have implicated the presenilins in the regulation of the Notch signaling pathway and in the pathogenesis of Alzheimer's Disease. There are two highly homologous presenilin genes in mammals, presenilin 1 (PS1) and presenilin 2 (PS2). In mice, inactivation of PS1 leads to developmental defects that culminate in a perinatal lethality. To test the possibility that the late lethality of PS1-null mice reflects genetic redundancy of the presenilins, we have generated PS2-null mice by gene targeting, and subsequently, PS1/PS2 double-null mice. Mice homozygous for a targeted null mutation in PS2 exhibit no obvious defects; however, loss of PS2 on a PS1-null background leads to embryonic lethality at embryonic day 9.5. Embryos lacking both presenilins, and surprisingly, those carrying only a single copy of PS2 on a PS1-null background, exhibit multiple early patterning defects, including lack of somite segmentation, disorganization of the trunk ventral neural tube, midbrain mesenchyme cell loss, anterior neuropore closure delays, and abnormal heart and second branchial arch development. In addition, Delta like-1 (Dll1) and Hes-5, two genes that lie downstream in the Notch pathway, were misexpressed in presenilin double-null embryos: Hes-5 expression was undetectable in these mice, whereas Dll1 was expressed ectopically in the neural tube and brain of double-null embryos. We conclude that the presenilins play a widespread role in embryogenesis, that there is a functional redundancy between PS1 and PS2, and that both vertebrate presenilins, like their invertebrate homologs, are essential for Notch signaling.