Deciphering the Mechanisms of Developmental Disorders (DMDD): a new programme for phenotyping embryonic lethal mice

Abstract

International efforts to test gene function in the mouse by the systematic knockout of each gene are creating many lines in which embryonic development is compromised. These homozygous lethal mutants represent a potential treasure trove for the biomedical community. Developmental biologists could exploit them in their studies of tissue differentiation and organogenesis; for clinical researchers they offer a powerful resource for investigating the origins of developmental diseases that affect newborns. Here, we outline a new programme of research in the UK aiming to kick-start research with embryonic lethal mouse lines. The 'Deciphering the Mechanisms of Developmental Disorders' (DMDD) programme has the ambitious goal of identifying all embryonic lethal knockout lines made in the UK over the next 5 years, and will use a combination of comprehensive imaging and transcriptomics to identify abnormalities in embryo structure and development. All data will be made freely available, enabling individual researchers to identify lines relevant to their research. The DMDD programme will coordinate its work with similar international efforts through the umbrella of the International Mouse Phenotyping Consortium [see accompanying Special Article (Adams et al., 2013)] and, together, these programmes will provide a novel database for embryonic development, linking gene identity with molecular profiles and morphology phenotypes.

Fig. 1.

Flow diagram of the DMDD programme. Embryo viability of homozygous nulls will be assessed 2 weeks after birth (P14) to identify EP lethal lines. Viability of EP embryos will then be checked at 14 days of gestation (E14.5) and viable embryos will be comprehensively imaged for malformations. If embryos are absent (resorbed), embryo litters will be examined after 9 or 10 days of gestation (E9.5–E10.5) and homozygous null embryos identified for imaging. All possible EP lines will be used for transcriptomics analysis at early stages of development. EP lines that appear normal at E14.5 will be reanalysed shortly before birth (E18.5) in order to detect neurological abnormalities. Data that will be presented on the DMDD web portal is indicated by pink boxes.

Fig. 2.

Overall DMDD workflow. Mouse lines identified as EP lethal will undergo analysis in the DMDD pipeline, with all anatomical and histological data scored for defects. Collective data for each line will be reviewed and published in full via the web portal.

Fig. 3.

Phenotyping embryos with high-resolution episcopic microscopy (HREM). Volume-rendered 3D models from HREM data allow the visualisation of embryo morphology at remarkably high resolution.