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A phenotype-based screen for embryonic lethal mutations in the mouse
A Kasarskis1, K Manova, K V Anderson
1Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, and the Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, 1275 York Avenue, New York, NY 10021, USA.
Abstract:
The genetic pathways that control development of the early mammalian embryo have remained poorly understood, in part because the systematic mutant screens that have been so successful in the identification of genes and pathways that direct embryonic development in Drosophila, Caenorhabditis elegans, and zebrafish have not been applied to mammalian embryogenesis. Here we demonstrate that chemical mutagenesis with ethylnitrosourea can be combined with the resources of mouse genomics to identify new genes that are essential for mammalian embryogenesis. A pilot screen for abnormal morphological phenotypes of midgestation embryos identified five mutant lines; the phenotypes of four of the lines are caused by recessive traits that map to single regions of the genome. Three mutant lines display defects in neural tube closure: one is caused by an allele of the open brain (opb) locus, one defines a previously unknown locus, and one has a complex genetic basis. Two mutations produce novel early phenotypes and map to regions of the genome not previously implicated in embryonic patterning.
Insights
This study introduces a new method for discovering genes controlling mammalian embryo development using chemical mutagenesis and mouse genomics. The approach identified new genes essential for early embryonic development and neural tube closure.
Area of Science:
- Developmental Biology
- Genetics
- Genomics
Background:
- Understanding genetic pathways in early mammalian embryo development is crucial but challenging.
- Systematic mutant screens, successful in other model organisms, have not been widely applied to mammalian embryogenesis.
Purpose of the Study:
- To demonstrate the utility of chemical mutagenesis combined with mouse genomics for identifying novel genes in mammalian embryogenesis.
- To identify genes essential for early embryonic development and neural tube closure in mammals.
Main Methods:
- Chemical mutagenesis using ethylnitrosourea in mice.
- Pilot screen for morphological phenotypes in midgestation embryos.
- Genetic mapping of identified mutant lines.
Main Results:
- Identified five mutant lines with abnormal midgestation embryonic phenotypes.
- Four lines exhibited recessive traits mapping to single genomic regions.
- Three lines showed defects in neural tube closure, including a known locus (opb) and a novel locus.
- Two mutations revealed novel early phenotypes in previously unlinked genomic regions.
Conclusions:
- Chemical mutagenesis and mouse genomics provide a powerful approach to uncover genes critical for mammalian embryogenesis.
- This method successfully identified new genes involved in neural tube development and early embryonic patterning.
- The findings open new avenues for research into the genetic control of mammalian development.