The investigators propose to conduct a large scale mutagenesis screen using the chemical mutagen N-ethyl-N-nitrosourea (ENU) to isolate recessive mutations that affect mammalian development. They will use a strategy that incorporates balancer chromosomes that cover approximately 25 percent of the mouse genome. These Cre-loxP engineered balancer chromosomes will be used as genetic tools to isolate region-specific mutations that result in all stages of embryonic or postpartum death. Mutations that result in embryonic death will be characterized by determining the stage of embryonic arrest, developmental histopathology, and a molecular profile through in situ hybridization. They will isolate viable mutations genome- wide using (1) X-ray analysis for skeletal and limb dysmorphology and bone density, (2) tandem mass spectrometry for biochemical metabolites, (3) urinalysis for glucose, and (4) a complete blood or urogenital abnormalities will be further characterized by endocrine tests. Mutations that result in death during neonatal to juvenile development will be displayed on a web site and distributed to the scientific community on request. Numerous human birth defects will be modeled including axial- limb patterning, neural tube and cardiac defects, and placental failure. Further, models of pediatric metabolic disorders and endocrinopathies will be isolated and characterized.
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