Analysis of Mouse Embryonic Patterning and Morphogenesis by Forward Genetics

Many aspects of the genetic control of mammalian embryogenesis cannot be extrapolated from other animals. Taking a forward genetic approach, we have induced recessive mutations by treatment of mice with ethylnitrosourea and have identified 43 mutations that affect early morphogenesis and patterning,...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 17; pp. 5913 - 5919
Main Authors García-García, María J., Eggenschwiler, Jonathan T., Caspary, Tamara, Alcorn, Heather L., Wyler, Michael R., Huangfu, Danwei, Rakeman, Andrew S., Lee, Jeffrey D., Feinberg, Evan H., Timmer, John R., Anderson, Kathryn V.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 26.04.2005
National Acad Sciences
SeriesInaugural Article
Subjects
Alleles
Animals
Biological Sciences
Body Patterning
Cardiac arrest
Chromosome Mapping
Embryos
Genes, Recessive
Genetic mutation
Genetic screening
Mammals
Mesoderm
Mice - embryology
Mice - genetics
Morphogenesis
Mutation
Nervous System - embryology
Neural tube defects
Neurons
Phenotypes
Species Specificity
Spinal cord
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Summary:Many aspects of the genetic control of mammalian embryogenesis cannot be extrapolated from other animals. Taking a forward genetic approach, we have induced recessive mutations by treatment of mice with ethylnitrosourea and have identified 43 mutations that affect early morphogenesis and patterning, including 38 genes that have not been studied previously. The molecular lesions responsible for 14 mutations were identified, including mutations in nine genes that had not been characterized previously. Some mutations affect vertebrate-specific components of conserved signaling pathways; for example, at least five mutations affect previously uncharacterized regulators of the Sonic hedgehog (Shh) pathway. Approximately half of all of the mutations affect the initial establishment of the body plan, and several of these produce phenotypes that have not been described previously. A large fraction of the genes identified affect cell migration, cellular organization, and cell structure. The findings indicate that phenotype-based genetic screens provide a direct and unbiased method to identify essential regulators of mammalian development.
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Present address: Department of Cell and Developmental Biology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10021.
Abbreviations: ENU, ethylnitrosourea; SSLP, simple sequence length polymorphism; en, embryonic day n; Smo, Smoothened; bnb, bent body; Hh, Hedgehog; IFT, intraflagellar transport; lzme, lazy mesoderm.
Present address: Department of Human Genetics, Emory University School of Medicine, Whitehead Research Building, 615 Michael Street, Suite 301, Atlanta, GA 30322.
Contributed by Kathryn V. Anderson, February 8, 2005
To whom correspondence should be addressed. E-mail: k-anderson@ski.mskcc.org.
Present address: Department of Molecular Biology, Princeton University Lewis Thomas Laboratory, Washington Road, LTL110, Princeton, NJ 08546.
This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on April 20, 2004.
See accompanying Biography on page 5910.
Author contributions: M.J.G.-G. and K.V.A. designed research; M.J.G.-G., J.T.E., T.C., H.L.A., M.R.W., D.H., A.S.R., J.D.L., E.H.F., J.R.T., and K.V.A. performed research; M.J.G.-G., J.T.E., and K.V.A. analyzed data; J.R.T. contributed new reagents/analytic tools; and M.J.G.-G. and K.V.A. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0501071102