NOTCH1 IS ESSENTIAL FOR POSTIMPLANTATION DEVELOPMENT IN MICE

The Notch gene of Drosophila encodes a large transmembrane protein inv olved in cell fate determination during embryonic and larval developme nt. This gene is evolutionarily conserved, and Notch homologs have bee n cloned from several vertebrate species. To examine the in vivo role of the Notch1 gene, a mouse homolog of Notch, a mutation was introduce d by targeted disruption in embryonic stem cells, and these cells were used to generate mutant mice. Intercrosses of animals heterozygous fo r the Notch1 mutation yielded no live-born homozygous mutant offspring . Homozygous mutant embryos died before 11.5 days of gestation. Morpho logical and histological analysis of the homozygous mutant embryos ind icated that pattern formation through the first nine days of gestation appeared largely normal. However, histological analysis of mutant emb ryos subsequent to this stage revealed widespread cell death. Death of mutant embryos did not appear to be attributable to defects in placen tation or vascularization. Examination of the RNA expression pattern o f 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 ea rly postimplantation development in mice.