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Background  Identifying developmental processes regulated by Notch1 can be addressed in part by characterizing mice with graded levels of Notch1 signaling strength. Here we examine development in embryos expressing various combinations of  Notch1  mutant alleles. Mice homozygous for the hypomorphic  Notch1  12 f   allele, which removes the single  O -fucose glycan in epidermal growth factor-like repeat 12 (EGF12) of the Notch1 ligand binding domain (lbd), exhibit reduced growth after weaning and defective T cell development. Mice homozygous for the inactive  Notch1   lbd   allele express Notch1 missing an ~20 kDa internal segment including the canonical Notch1 ligand binding domain, and die at embryonic day ~E9.5. The embryonic and vascular phenotypes of compound heterozygous  Notch1  12 f / lbd   embryos were compared with  Notch1  +/12 f  ,  Notch1  12 f /12 f  , and  Notch1   lbd / lbd   embryos. Embryonic stem (ES) cells derived from these embryos were also examined in Notch signaling assays. While Notch1 signaling was stronger in  Notch1  12 f / lbd   compound heterozygotes compared to  Notch1   lbd / lbd   embryos and ES cells, Notch1 signaling was even stronger in embryos carrying  Notch1  12 f   and a null  Notch1  allele.    Results  Mouse embryos expressing the hypomorphic  Notch1  12 f   allele, in combination with the inactive  Notch1   lbd   allele which lacks the Notch1 ligand binding domain, died at ~E11.5-12.5.  Notch1  12 f / lbd   ES cells signaled less well than  Notch1  12 f /12 f   ES cells but more strongly than  Notch1   lbd / lbd   ES cells. However, vascular defects in  Notch1  12 f / lbd   yolk sac were severe and similar to  Notch1   lbd / lbd   yolk sac. By contrast, vascular disorganization was milder in  Notch1  12 f / lbd   compared to  Notch1   lbd / lbd   embryos. The expression of Notch1 target genes was low in  Notch1  12 f / lbd   yolk sac and embryo head, whereas Vegf and Vegfr2 transcripts were increased. The severity of the compound heterozygous  Notch1  12 f / lbd   yolk sac phenotype suggested that the allelic products may functionally interact. By contrast, compound heterozygotes with  Notch1  12 f   in combination with a  Notch1  null allele ( Notch1  tm1Con ) were capable of surviving to birth.    Conclusions  Notch1 signaling in  Notch1  12 f / lbd   compound heterozygous embryos is more defective than in compound heterozygotes expressing a hypomorphic  Notch1  12 f   allele and a  Notch1  null allele. The data suggest that the gene products Notch1 lbd  and Notch1 12f  interact to reduce the activity of Notch1 12f .

Effects of varying Notch1 signal strength on embryogenesis and vasculogenesis in compound mutant heterozygotes