Abstract:
The Notch gene of Drosophila encodes a large transmembrane protein involved in cell fate determination during embryonic and larval development. This gene is evolutionarily conserved, and Notch homologs have been cloned from several vertebrate species. To examine the in vivo role of the Notch1 gene, a mouse homolog of Notch, a mutation was introduced by targeted disruption in embryonic stem cells, and these cells were used to generate mutant mice. Intercrosses of animals heterozygous for the Notch1 mutation yielded no live-born homozygous mutant offspring. Homozygous mutant embryos died before 11.5 days of gestation. Morphological and histological analysis of the homozygous mutant embryos indicated that pattern formation through the first nine days of gestation appeared largely normal. However, histological analysis of mutant embryos subsequent to this stage revealed widespread cell death. Death of mutant embryos did not appear to be attributable to defects in placentation or vascularization. Examination of the RNA expression pattern of the Notch2 gene, another Notch gene family member, indicated that it partially overlapped the Notch1 expression pattern. Genetic analysis of the Notch1 mutation also demonstrated that it was not allelic to a mouse mutation described previously, Danforth\'s short tail (Sd). These results demonstrate that the Notch1 gene plays a vital role during early postimplantation development in mice.
摘要:
果蝇的Notch基因编码一种大型跨膜蛋白,参与胚胎和幼虫发育过程中的细胞命运决定。这个基因在进化上是保守的,和Notch同源物已经从几种脊椎动物物种中克隆出来。为了检查Notch1基因的体内作用,Notch的老鼠同源物,通过胚胎干细胞的靶向破坏引入突变,这些细胞被用来产生突变小鼠。Notch1突变的杂合动物的杂交没有产生活产纯合突变后代。纯合突变胚胎在妊娠11.5天之前死亡。纯合突变胚胎的形态和组织学分析表明,在妊娠的前9天,模式形成似乎很正常。然而,此阶段之后的突变胚胎的组织学分析显示广泛的细胞死亡。突变胚胎的死亡似乎并非归因于胎盘形成或血管形成的缺陷。检测Notch2基因的RNA表达模式,另一个Notch基因家族成员,表明它与Notch1表达模式部分重叠。Notch1突变的遗传分析还表明,它不是先前描述的小鼠突变的等位基因,丹佛斯的短尾(Sd)。这些结果表明,Notch1基因在小鼠植入后的早期发育中起着至关重要的作用。