Abstract
SummaryInternational 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.
Highlights
Experience gained over more than a decade of mouse transgenics work has revealed that approximately half of all mouse gene knockouts demonstrating recessive embryonic or perinatal (EP) lethality complete the major period of organogenesis (E14.5-E15.5) and reach a point when organ arrangement resembles that of the adult
Existing phenotyping efforts show that at least 60% of all EP lethals studied to date have readily detectable structural defects in one or more organ systems. (The true figure is likely to be significantly higher because existing studies have rarely been systematic, nor have they used consistent or comparable imaging methods.) Taken together, these observations indicate that simple screening of embryo morphology provides a remarkably efficient way to identify genes that are important in embryo development and organogenesis
As a first step towards identifying the cellular processes and molecular pathways that are disrupted by gene deletion, the Developmental Disorders’ (DMDD) programme will complement morphological analysis by analysing the transcriptome of knockout embryos, using RNA sequencing (RNA-seq)
Summary
Experience gained over more than a decade of mouse transgenics work has revealed that approximately half of all mouse gene knockouts demonstrating recessive EP lethality complete the major period of organogenesis (E14.5-E15.5) and reach a point when organ arrangement resembles that of the adult. (The true figure is likely to be significantly higher because existing studies have rarely been systematic, nor have they used consistent or comparable imaging methods.) Taken together, these observations indicate that simple screening of embryo morphology provides a remarkably efficient way to identify genes that are important in embryo development and organogenesis. At least 240 of these lines will provide viable embryos, either at mid-gestation or after organogenesis, and will be amenable to analysis This will dramatically extend the pool of mouse genes known to be critical for normal embryo development, enhancing research into the genetic networks that are responsible for tissue organisation and organogenesis. For a large proportion of these mutants, the gene knockout will affect later aspects of neural development, and will not be detected using simple morphological criteria These mutations result in severe defects (for example, in movement, breathing, cognition, vision or suckling) that render the pups unviable. Histological analysis will be used to detect late-appearing phenotypes such as craniosynostosis, hindbrain herniation (Chiari II defect) and submucous cleft palate, whereas immunohistochemistry will identify defects in synaptogenesis and neuronal differentiation or morphology
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