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The Notch signalling pathway has a central role in a wide variety of developmental processes and it is not therefore surprising that mutations in components of this pathway can cause dramatic human genetic disorders. One developmental process in which the Notch pathway is involved at multiple levels is somitogenesis, the mechanism by which the embryo is divided into segments that ultimately form structures such as the axial skeleton and skeletal muscle of the trunk. We are investigating the human genetic disorder spondylocostal dysplasia (SCD), which is a group of malsegmentation syndromes that occur when this process is disrupted. Mutations in the Notch ligand DELTA-LIKE 3 (DLL3) are responsible for cases of autosomal recessive SCD type I (SCDO1), and we are using information derived from these mutations to study the structure of the DLL3 protein. To aid in elucidation of the underlying developmental defect in SCDO1, we have generated a mouse model by targeted deletion of the Dll3 gene (Dunwoodie et al., 2002). These mice show segmentation defects similar to those seen in SCDO1. In addition, these mice have a distinct set of neural defects that may be useful in future neurological assessment of affected individuals. Finally, since not all cases of SCD are due to mutation of DLL3, we are investigating various genes to find other candidates involved in this genetic disease.

Type

Journal article

Journal

Int j dev biol

Publication Date

2002

Volume

46

Pages

365 - 374

Keywords

Animals, Bone Diseases, Developmental, Brain, DNA Primers, Dementia, Multi-Infarct, Gene Expression Regulation, Developmental, Humans, In Situ Hybridization, Intracellular Signaling Peptides and Proteins, Ligands, Membrane Proteins, Mice, Mutation, Polymorphism, Genetic, Proto-Oncogene Proteins, Receptor, Notch4, Receptors, Cell Surface, Receptors, Notch, Signal Transduction, Time Factors