Dll3 and Notch1 genetic interactions model axial segmental and craniofacial malformations of human birth defects

Mutations in the Notch1 receptor and delta-like 3 (Dll3) ligand cause global disruptions in axial segmental patterning. Genetic interactions between members of the notch pathway have previously been shown to cause patterning defects not observed in single gene disruptions. We examined Dll3-Notch1 compound mouse mutants to screen for potential gene interactions. While mice heterozygous at either locus appeared normal, 30% of Dll3-Notch1 double heterozygous animals exhibited localized, stochastic segmental anomalies similar to human congenital vertebral defects. Unexpectedly, double heterozygous mice also displayed statistically significant decreases in mandibular height and elongated maxillary hard palate. Examination of somite-stage embryos and perinatal anatomy and histology did not reveal any organ defects, so we used microarray-based analysis of Dll3 and Notch1 mutant embryos to identify gene targets that may be involved in notch-regulated segmental or craniofacial development. Therefore, Dll3-Notch1 double heterozygous mice model human congenital scoliosis and craniofacial disorders.

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Loomes KM, Stevens SA, O'Brien ML, Gonzalez DM, Ryan MJ, Segalov M, Dormans NJ, Mimoto MS, Gibson JD, Sewell W, Schaffer AA, Nah HD, Rappaport EF, Pratt SC, Dunwoodie SL, Kusumi K