Streamline assessment of early lethal phenotypes in the mouse Although the generation of a loss of function allele at every locus in the mouse genome is well underway, there is a gap in established pipelines for assessment of early lethal phenotypes (as stated in PAR-17-005). Here we propose to continue our efforts to characterize up to 150 early lethal phenotypes occurring between fertilization and organogenesis. As described within, we have instituted an efficient strategy to analyze early lethal phenotypes and have already analyzed more than 100 novel phenotypes. We will provide a tremendous amount of novel data to the scientific community and foster collaborative efforts towards functional annotation of the mammalian genome. The proposed work capitalizes on techniques that our groups perform and publish routinely, maximizing the data generation by eliminating training/troubleshooting steps as well as boosting our individual research programs by providing novel phenotypes of interest. Characterization of knock-out alleles will be invaluable towards understanding genetic pathways and predicting mechanisms of diseases/phenotypes found in adults ? in both heterozygotes and homozygous knockouts of genes in gene/protein networks or pathways. We will provide detailed morphogenetic characterization for each mutant phenotype. Characterization of novel gastrulation and preimplantation phenotypes will complement and extend our current morphogenetic understanding of early developmental events. Our proposal dovetails perfectly with existing phenotyping efforts and fills an essential need to characterize early lethal phenotypes towards functional annotation of the genome.

Public Health Relevance

The ongoing international effort to generate a loss of function knock-out (KO) allele for every gene in mouse is well underway. However, 12% of homozygous knock-out mice will be embryonic lethal prior to E9.5 and there is no current plan to analyze them. During the first award period we have capitalized on the immense resource that these knock-out alleles provide by characterizing more than 100 novel early embryonic lethal phenotypes. Here we propose to continue our streamlined assessment of up to 150 knock out alleles. These studies will enhance our understanding of the initial stages of development of early cell lineages, multiple organ progenitors as well as advance our understanding of human disease by identifying specific gene functions during critical developmental events. Our proposal fills the existing gap in phenotyping efforts and will maximize the productivity of the IMPC and KOMP efforts in generating KO alleles at every gene.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Development - 1 Study Section (DEV1)
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Mukhopadhyay, Mahua
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University of Massachusetts Amherst
Veterinary Sciences
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United States
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Cui, Wei; Marcho, Chelsea; Wang, Yongsheng et al. (2018) Med20 is essential for early embryogenesis and regulates Nanog expression. Reproduction :
Yoon, Yeonsoo; Wang, Dan; Tai, Phillip W L et al. (2018) Streamlined ex vivo and in vivo genome editing in mouse embryos using recombinant adeno-associated viruses. Nat Commun 9:412
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