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Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm

¹ Division of Mammalian Development, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK
² Developmental Biology Unit, The Victor Chang Cardiac Research Institute, 384 Victoria Street, Darlinghurst, NSW 2010, Australia
³ Department of Genetics, Case Western Reserve University, and University Hospitals Cleveland, 10900 Euclid Avenue, Cleveland, OH 44106-4955, USA

*Author for correspondence (e-mail: s.dunwoodie{at}victorchang.unsw.edu.au)

This article is dedicated to Rosa Beddington (March 23, 1956 to May 18, 2001) an extraordinary embryologist and a great friend

Accepted 14 December 2001

A loss-of-function mutation in the mouse delta-like3 (Dll3) gene has been generated following gene targeting, and results in severe axial skeletal defects. These defects, which consist of highly disorganised vertebrae and costal defects, are similar to those associated with the Dll3-dependent pudgy mutant in mouse and with spondylocostal dysplasia (MIM 277300) in humans. This study demonstrates that Dll3^neo and Dll3^pu are functionally equivalent alleles with respect to the skeletal dysplasia, and we suggest that the three human DLL3 mutations associated with spondylocostal dysplasia are also functionally equivalent to the Dll3^neo null allele. Our phenotypic analysis of Dll3^neo/Dll3^neo mutants shows that the developmental origins of the skeletal defects lie in delayed and irregular somite formation, which results in the perturbation of anteroposterior somite polarity. As the expression of Lfng, Hes1, Hes5 and Hey1 is disrupted in the presomitic mesoderm, we suggest that the somitic aberrations are founded in the disruption of the segmentation clock that intrinsically oscillates within presomitic mesoderm.

Key words: Notch signalling, Somite, Spondylocostal dysplasia, Pudgy, Dll3, Mouse

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