The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries

Abstract

Pudgy (pu) homozygous mice exhibit clear patterning defects at the earliest stages of somitogenesis, resulting in adult mice with severe vertebral and rib deformities. By positional cloning and complementation, we have determined that the pu phenotype is caused by a mutation in the delta-like 3 gene (Dll3), which is homologous to the Notch-ligand Delta in Drosophila. Histological and molecular marker analyses show that the pu mutation disrupts the proper formation of morphological borders in early somite formation and of rostral-caudal compartment boundaries within somites. Viability analysis also indicates an important role in early development. The results point to a key role for a Notch-signalling pathway in the initiation of patterning of vertebrate paraxial mesoderm.

Abnormal vertebral segmentation and the notch signaling pathway in man

“…Spinal cord compression and associated neurological features have not been observed in SCD1, and intelligence and cognitive performance are normal. This finding suggests that DLL3 is not expressed in human brain, which contrasts to findings in the mouse, where central nervous system defects have been found , including defects in the neuroventricles of the Pudgy mouse (Kusumi et al, 1998;Dunwoodie et al, 2002).…”

“…The locus identified, 19q13.1, is syntenic with mouse chromosome 7 (Giampietro et al, 1999), which harbors the Dll3 gene. The other key breakthrough was the identification of a mutation in Dll3 as the cause of MVSD in a radiation-damaged mouse known as Pudgy (Grü neberg, 1961;Dunwoodie et al, 1997;Kusumi et al, 1998). DLL3 was, therefore, the obvious candidate SCD in the large inbred Arab kindred, and other families, demonstrating linkage to 19q13.1.…”

“…The extent to which this process directly correlates with somitogenesis in man is unknown, except that the phenotypes of the Mesp2 and Dll3 mutant mice bear a resemblance to human SCD (Saga et al, 1997;Kusumi et al, 1998;Dunwoodie et al, 2002). The findings in this one family provided the first evidence that MESP2 is critical for normal somitogenesis in man.…”

The long and short of it: Somite formation in mice

“…Several years ago, Bulman and colleagues demonstrated that one form of autosomal recessive spondylocostal dysostosis was caused by mutations in the gene encoding the Notch ligand DLL3 (Bulman et al, 2000). The phenotype exhibited by human patients closely resembles the phenotype exhibited by mice homozygous for loss of function mutations of the Dll3 gene (Kusumi et al, 1998;Dunwoodie et al, 2002). Recently, two other genes intimately associated with the Notch pathway have been shown to cause autosomal recessive spondylocostal dysostosis.…”

“…The Lunatic fringe (Lfng) gene encodes a glycosyltransferase that modifies O-fucose residues in Notch family proteins, thereby modulating Notch signal transmission (Haltiwanger and Lowe, 2004). Previous comparative analysis of mouse models had demonstrated that mice mutant for the Dll3 and Lfng genes exhibited very similar somite and skeletal defects (Evrard et al, 1998;Kusumi et al, 1998Kusumi et al, , 2004Zhang and Gridley, 1998;Dunwoodie et al, 2002;Zhang et al, 2002), suggesting the LFNG gene as another possible spondylocostal dysostosis gene in humans. Using a candidate gene approach, Sparrow and colleagues identified a LFNG mutation in a single family with autosomal recessive spondylocostal dysostosis (Sparrow et al, 2006).…”