New Mutant Mouse with Skeletal Deformities Caused by Mutation in Delta Like 3 (Dll3) Gene.

Abstract

Abstract:We have established a new mouse strain with vertebral deformities caused by an autosomal single recessive mutation (oma). The mutant mice showed short trunk and short and kinky tail. The skeletal preparations of newborn and prenatal mice showed disorganized vertebrae and numerous vertebral and rib fusions which are thought to be caused by patterning defects at the stage of somitegenesis. Linkage analysis localized the oma locus on the proximal region of mouse chromosome 7 close to Dll3 gene. Dll3 is the gene involved in the Notch signaling pathway and null-mutation of the gene has been reported to cause vertebral deformities. The phenotypic similarity between oma and Dll3 null-mutant mice suggests that the causative gene for the oma mutant is the Dll3 gene. We, therefore, investigated the nucleotide sequence of the Dll3 gene of the oma mouse and found a single nucleotide substitution of G to T which causes missense mutation of glycine to cysteine at codon 409. Since the amino acid substitution is a nonconservative amino acid substitution at the conserved portion of the Dll3 protein, and the substitution is specific to the mutant mice, we concluded that the nucleotide substitution of the Dll3 gene is responsible for the skeletal deformities of the oma mouse.

VACTERL anomalies in patients with esophageal atresia: an updated delineation of the spectrum and review of the literature

“…This sequence is conserved among mammals and defects within have been previously found in mice with vertebral defects [11]. The relationship of this sequence to the Shh and its downstream genes remains unclear, however, we would suspect that separate pathways without interaction accounting for the VACTERL complex is unlikely.…”

Progress in the Understanding of the Genetic Etiology of Vertebral Segmentation Disorders in Humans

“…Gene targeting generated the DLL3 neo null allele in which the DSL, EGF‐like repeats, and transmembrane domain were deleted 19 . DLL3 oma is a spontaneously arising allele whereby a single nucleotide substitution in EGF‐like repeat‐5 results in a glycine to cysteine conversion at amino acid 409 32 . DLL3 ‐null mice are easily identified during gestation by virtue of the vertebral column that is drastically shortened along its entire length and exhibits a mixture of irregular fused vertebrae and incompletely developed vertebral bodies interspersed with occasional normal vertebrae (Fig.…”

“…In humans, PAX1 mutations have been reported to occur in 6 of 63 patients with Klippel−Feil syndrome 102 WNT3A: WNT3A is necessary for generation of the posterior portion of the neuraxis, since knockout mice fail to develop a tail bud and are truncated from a point slightly anterior to the hindlimbs 32 . This gene is a member of a moderate‐sized multigene family comprising at least 12 members in humans and the mouse.…”

Characterization of the Skeletal Fusion with Sterility (<i>sks</i>) Mouse Showing Axial Skeleton Abnormalities Caused by Defects of Embryonic Skeletal Development

“…[6], and Shinkai et al. [23] reported a short trunk and short, kinky tail in mice with a mutation of the delta-like 3 (Drosophila) ( Dll3 ) gene. Neonatal Dll3 –/– mice have a highly disorganized axial skeleton with numerous vertebral and rib fusions, and the underlying phenotype is suggested to be a defectively formed and segmented sclerotome caused by patterning defects of somitogenesis.…”