title: Dll3 and Notch1 genetic interactions model axial segmental and craniofacial malformations of human birth defects.
abstract: 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 decreased length of the [corrected] 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.
authors.affiliation: Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Loomes
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Stevens
authors.forename: Megan L
authors.initials: ML
authors.lastname: O'Brien
authors.forename: Dorian M
authors.initials: DM
authors.lastname: Gonzalez
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ryan
authors.forename: Michelle
authors.initials: M
authors.lastname: Segalov
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Dormans
authors.forename: Mizuho S
authors.initials: MS
authors.lastname: Mimoto
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Gibson
authors.forename: William
authors.initials: W
authors.lastname: Sewell
authors.forename: Alyssa A
authors.initials: AA
authors.lastname: Schaffer
authors.forename: Hyun-Duck
authors.initials: HD
authors.lastname: Nah
authors.forename: Eric F
authors.initials: EF
authors.lastname: Rappaport
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pratt
authors.forename: Sally L
authors.initials: SL
authors.lastname: Dunwoodie
authors.forename: Kenro
authors.initials: K
authors.lastname: Kusumi
mesh_terms: D000818:Animals; D019521:Body Patterning; D002508:Cephalometry; D000013:Congenital Abnormalities / Q000196:embryology / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000235:genetics*; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008334:Mandible / Q000002:abnormalities; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D021362:Palate, Hard / Q000002:abnormalities; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D012272:Ribs / Q000002:abnormalities; D012600:Scoliosis / Q000235:genetics*; D013131:Spine / Q000002:abnormalities
chemical_list: C511877:Dll3 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1