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Delta-like1 haploinsufficiency – Smaller, lighter, weaker?

Delta-like 1 (Dll1) is a ligand of Notch receptor proteins. The Notch signalling pathway is an intercellular signalling mechanism that is highly conserved during evolution of vertebrates. It is involved in the determination of cell fates in different cell types during embryonic development. Notch signalling has many diverse roles in physiology and pathology, as can be seen when a loss- or gain-of-function of the Notch receptors or their ligands occurs. Diverse and often severe clinical, physiological and biological effects in humans are the consequence (e.g. T-cell acute lymphoblastic leukemia, diseases of the heart (cardiomyopathies), Alagille syndrome, cerebral arteriopathy autosomal dominant disease with subcortical infarcts and leukoencephalopathy (CADASIL), spondylocostal dysostosis). Notch signalling and associated diseases involve not only these inherited disorders. Notch signalling seems to be also involved in tumour associated growth of small blood vessels and tissue regeneration of adult organs (heart, liver, brain, kidney and pancreas) after injury.

If the Dll1 protein is missing in the organism, mouse embryos die during development in the womb. But what happens if only one copy of the Dll1 gene (allele) is active? To answer this question, the scientists around Isabel Rubio-Aliaga analysed adult animals with reduced levels of Dll1 (haploinsufficiency) (Dll1tm1Gos/+) and animals carrying a mutation in the Dll1 gene leading to a change in an important segment of the protein (Dll1C413Y) in the German Mouse Clinic (GMC).

When these animals were compared to each other it became obvious that they both are different from wild-type animals: both were smaller, lighter, had reduced bone mass density and bone mineral content, reduced fat mass, slower pulse rate but increased blood pressure and reduced amounts of cholesterol and other fat molecules in the blood. However, they also showed differences from each other. The haploinsufficient mice had less muscle tissue and urea in the blood compared to the mice with a mutation in the Dll1 gene. Changes in the immune cells populations were found in the haploinsufficient but not the other mutant mice.

The results show that even slight alterations in one player of Notch signalling alter several biological processes in the entire organism. The analysed alterations emphasize the importance of Dll1 mainly for metabolism, energy balance and in immunology. Since disturbed Notch signalling plays an important role in several severe human diseases the influence of the diverse interaction partners in the Notch pathway is important to understand the aetiology of these conditions.

 

Dll1 Haploinsufficiency in Adult Mice Leads to a Complex Phenotype Affecting Metabolic and Immunological Processes“, Rubio-Aliaga et al., PLoS ONE, 2009 4 (6), e6054