The previous cycles of this grant have supported our efforts to generate models of human congenital defects by screening ENU-mutagenized mice for recessive mutations affecting late embryonic development. These screens incorporated a genetic mapping component to facilitate the positional cloning and functional characterization of the mutant genes. The strategy has worked well, and we have generated many mice with phenotypes similar to human malformation syndromes and birth defects. Our future effort has even greater potential productivity, as the overall task of mutation discovery continues to be facilitated by rapid progress in technologies for genomic analysis. In this continuation proposal we aim to optimize several aspects of the project, while maintaining the fundamental approach that has thus far proven so productive. Specifically, we propose strategies for rapid mutant validation and for more rapidly translating gene discovery into functional analysis.
We are able to identify mutations causing abnormalities of organ development by systematically screening mice treated with the chemical mutagen ENU. The generation of powerful tools for genome analysis allows us to rapidly identify the gene mutated in these abnormal mice. This provides insight into the causes of congenital birth defects and the basic biology of human development.
|Jacobs, Damon T; Silva, Luciane M; Allard, Bailey A et al. (2016) Dysfunction of intraflagellar transport-A causes hyperphagia-induced obesity and metabolic syndrome. Dis Model Mech 9:789-98|
|Gallego-Llamas, Jabier; Timms, Andrew E; Pitstick, Rose et al. (2016) Improvement of ENU Mutagenesis Efficiency Using Serial Injection and Mismatch Repair Deficiency Mice. PLoS One 11:e0159377|
|Ha, Seungshin; Lindsay, Anna M; Timms, Andrew E et al. (2016) Mutations in Dnaaf1 and Lrrc48 Cause Hydrocephalus, Laterality Defects, and Sinusitis in Mice. G3 (Bethesda) 6:2479-87|
|Czarnecki, Peter G; Gabriel, George C; Manning, Danielle K et al. (2015) ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning. Nat Commun 6:6023|
|Menke, Chelsea; Cionni, Megan; Siggers, Trevor et al. (2015) Grhl2 is required in nonneural tissues for neural progenitor survival and forebrain development. Genesis :|
|Gallego-Llamas, Jabier; Timms, Andrew E; Geister, Krista A et al. (2015) Variant mapping and mutation discovery in inbred mice using next-generation sequencing. BMC Genomics 16:913|
|Ha, Seungshin; Stottmann, Rolf W; Furley, Andrew J et al. (2015) A forward genetic screen in mice identifies mutants with abnormal cortical patterning. Cereb Cortex 25:167-79|
|Stottmann, Rolf; Beier, David (2014) ENU mutagenesis in the mouse. Curr Protoc Mouse Biol 4:25-35|
|Stottmann, Rolf; Beier, David (2014) ENU Mutagenesis in the Mouse. Curr Protoc Hum Genet 82:15.4.1-10|
|Tran, Pamela V; Talbott, George C; Turbe-Doan, Annick et al. (2014) Downregulating hedgehog signaling reduces renal cystogenic potential of mouse models. J Am Soc Nephrol 25:2201-12|
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