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

• Published in: Developmental dynamics 2007-10, Vol.236 (10), p.2943-2951
• Main Authors: Loomes, Kathleen M., Stevens, Stacey A., O'Brien, Megan L., Gonzalez, Dorian M., Ryan, Matthew J., Segalov, Michelle, Dormans, Nicholas J., Mimoto, Mizuho S., Gibson, Joshua D., Sewell, William, Schaffer, Alyssa A., Nah, Hyun‐Duck, Rappaport, Eric F., Pratt, Stephen C., Dunwoodie, Sally L., Kusumi, Kenro
• Format: Article
• Language: English
• Subjects: Animals; Body Patterning; Cephalometry; Congenital Abnormalities - embryology; Congenital Abnormalities - genetics; craniofacial; Craniofacial Abnormalities - genetics; Disease Models, Animal; Dll3; Gene Expression Regulation, Developmental; hard palate; Heterozygote; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; mandible; Mandible - abnormalities; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Mutant Strains; notch pathway; Notch1; Oligonucleotide Array Sequence Analysis; Palate, Hard - abnormalities; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Ribs - abnormalities; Scoliosis - genetics; segmentation; skeletal; somite; Spine - abnormalities; vertebral
• ISSN: 1058-8388; 1097-0177
• DOI: 10.1002/dvdy.21296

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, segmental anomalies similar to human congenital vertebral defects. Unexpectedly, double heterozygous mice also displayed statistically significant reduction of mandibular height and elongation of 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. Thus, Dll3‐Notch1 double heterozygous mice model human congenital scoliosis and craniofacial disorders. Developmental Dynamics 236:2943–2951, 2007. © 2007 Wiley‐Liss, Inc.