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Background  Mouse NOTCH1 carries a highly conserved O-fucose glycan at Thr466 in epidermal growth factor-like repeat 12 (EGF12) of the extracellular domain. O-Fucose at this site has been shown by X-ray crystallography to be recognized by both DLL4 and JAG1 Notch ligands. We previously showed that a  Notch1  Thr466Ala mutant exhibits very little ligand-induced NOTCH1 signaling in a reporter assay, whereas a Thr466Ser mutation enables the transfer of O-fucose and reverts the NOTCH1 signaling defect. We subsequently generated a mutant mouse with the Thr466Ala mutation termed  Notch1 [12f]( Notch1  tm2Pst ). Surprisingly, homozygous  Notch1 [12f/12f] mutants on a mixed background were viable and fertile.    Results  We now report that after backcrossing to C57BL/6 J mice for 11–15 generations, few homozygous  Notch1 [12f/12f] embryos were born. Timed mating showed that embryonic lethality occurred by embryonic day (E) ~E11.5, somewhat delayed compared to mice lacking  Notch1  or  Pofut1  (the O-fucosyltransferase that adds O-fucose to Notch receptors), which die at ~E9.5. The phenotype of C57BL/6 J  Notch1 [12f/12f] embryos was milder than mutants affected by loss of a canonical Notch pathway member, but disorganized vasculogenesis in the yolk sac, delayed somitogenesis and development were characteristic. In situ hybridization of Notch target genes  Uncx4.1  and  Dll3  or western blot analysis of NOTCH1 cleavage did not reveal significant differences at E9.5. However, qRT-PCR of head cDNA showed increased expression of  Dll3 ,  Uncx4.1  and  Notch1  in E9.5  Notch1 [12f/12f] embryos. Sequencing of cDNA from  Notch1 [12f/12f] embryo heads and Southern analysis showed that the  Notch1 [12f] locus was intact following backcrossing. We therefore looked for evidence of modifying gene(s) by crossing C57BL/6 J  Notch1  [12f/+] mice to 129S2/SvPasCrl mice. Intercrosses of the F1 progeny gave viable F2  Notch1 [12f/12f] mice.    Conclusion  We conclude that the 129S2/SvPasCrl genome contains a dominant modifying gene that rescues the functions of NOTCH1[12f] in signaling. Identification of the modifying gene has the potential to illuminate novel factor(s) that promote Notch signaling when an O-fucose glycan is absent from EGF12 of NOTCH1.

A modifier in the 129S2/SvPasCrl genome is responsible for the viability of Notch1[12f/12f] mice