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

DOI: 10.1186/1471-213x-10-36

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Abstract:

Mouse embryos expressing the hypomorphic Notch112f allele, in combination with the inactive Notch1lbd allele which lacks the Notch1 ligand binding domain, died at ~E11.5-12.5. Notch112f/lbd ES cells signaled less well than Notch112f/12f ES cells but more strongly than Notch1lbd/lbd ES cells. However, vascular defects in Notch112f/lbd yolk sac were severe and similar to Notch1lbd/lbd yolk sac. By contrast, vascular disorganization was milder in Notch112f/lbd compared to Notch1lbd/lbd embryos. The expression of Notch1 target genes was low in Notch112f/lbd yolk sac and embryo head, whereas Vegf and Vegfr2 transcripts were increased. The severity of the compound heterozygous Notch112f/lbd yolk sac phenotype suggested that the allelic products may functionally interact. By contrast, compound heterozygotes with Notch112f in combination with a Notch1 null allele (Notch1tm1Con) were capable of surviving to birth.Notch1 signaling in Notch112f/lbd compound heterozygous embryos is more defective than in compound heterozygotes expressing a hypomorphic Notch112f allele and a Notch1 null allele. The data suggest that the gene products Notch1lbd and Notch112f interact to reduce the activity of Notch112f.Notch transmembrane receptors are important regulators of cell fate determination in numerous cell types [1-3]. Notch receptors in Drosophila and mammals are covalently modified with O-fucose on many epidermal growth factor-like (EGF) repeats of the extracellular domain [4]. An important O-fucose site resides in epidermal growth factor-like repeat 12 (EGF12) which, together with EGF11, is required for canonical Notch ligand binding to Drosophila Notch [5-7] and to mammalian Notch1 [8]. A point mutation that precludes the addition of fucose to EGF12 in Drosophila Notch results in enhanced binding of both Delta and Serrate Notch ligands, and a hyperactive Notch that is refractory to Fringe [9]. However, the same mutation (Notch112f) in cultured mammalian cells gives markedly reduced

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