Abstract
Background: Identifying genes that are essential for mouse embryonic development and survival through term is a powerful and unbiased way to discover possible genetic determinants of human developmental disorders. Characterising the changes in mouse embryos that result from ablation of lethal genes is a necessary first step towards uncovering their role in normal embryonic development and establishing any correlates amongst human congenital abnormalities. Methods: Here we present results gathered to date in the Deciphering the Mechanisms of Developmental Disorders (DMDD) programme, cataloguing the morphological defects identified from comprehensive imaging of 220 homozygous mutant and 114 wild type embryos from 42 lethal and subviable lines, analysed at E14.5. Results: Virtually all mutant embryos show multiple abnormal phenotypes and amongst the 42 lines these affect most organ systems. Within each mutant line, the phenotypes of individual embryos form distinct but overlapping sets. Subcutaneous edema, malformations of the heart or great vessels, abnormalities in forebrain morphology and the musculature of the eyes are all prevalent phenotypes, as is loss or abnormal size of the hypoglossal nerve.Conclusions: Overall, the most striking finding is that no matter how profound the malformation, each phenotype shows highly variable penetrance within a mutant line. These findings have challenging implications for efforts to identify human disease correlates.
Highlights
Animal models have long been used as experimental surrogates for investigating the role of individual genes in human development and disease
Gene knockout lines produced as part of a systematic programme coordinated by the International Mouse Phenotyping Consortium were designated lethal if no homozygous mutants were present amongst a minimum of 28 pups at P14 and sub-viable if their proportion fell below 13% of total offspring[2]
Size of the study The data for this study comprises 220 homozygous mutant and 114 wild type E14.5 embryos analysed by the Developmental Disorders (DMDD) programme
Summary
Animal models have long been used as experimental surrogates for investigating the role of individual genes in human development and disease. In generating KO lines from about one quarter of the total mouse genome so far, these studies have revealed that around one third of all mammalian genes are essential for life[1,2,3], their removal resulting in embryonic or perinatal lethality. The study of such mutant lines provides a unique opportunity to gain a comprehensive overview of the genetic components regulating normal embryo development and, by inference, the identity of genes whose mutation may cause congenital abnormalities or developmental disease. Conclusions: Overall, the most striking finding is that no matter how version 2
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
