? This project seeks to continue studies that were originally funded as part of an Interactive Research Project Grant (IRPG). The goal of the project was to perform functional analyses of an approximately 30 cM region of mouse Chromosome 5 using region-specific saturation mutagenesis with the point mutagen, ethylnitrosourea (ENU). Mice were screened for mutations causing embryonic lethality, infertility, behavioral defects, deafness, genome instability and eye defects. A set of chromosomal deletion complexes was created that spanned much of the target region, allowing a simple and rapid way to genetically map the identified mutations in complementation tests. The major aim of this work will be to characterize, genetically and phenotypically, the collection of mutations (projected to be 40-50) in greater detail. Most of the mutations we identified were embryonic lethal on Chr 5, detected on the basis of a """"""""loss-of-genotypic class"""""""" in the mating scheme. The timing and nature of developmental defects leading to the lethalities will be evaluated. The collection of deletions will be used to map the ENU induced mutations to small intervals and assemble them into complementation groups. One semilethal mutation causing skeletal patterning defects will be positionally cloned, as will a male sterility mutation resulting in severe sperm motility defects.
The second aim i s to explore the genetic basis for a haploinsufficiency phenotype, revealed by certain deletions, that model the Wolf-Hirschhorn contiguous gene syndrome. This disease causes mental retardation, skeletal dysmorphology, midline defects, and seizures. A combination of deletion mapping and BAC transgene complementation will be used to identify those regions responsible for components of the phenotype in mice. ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD035984-07
Application #
6758011
Study Section
Genome Study Section (GNM)
Program Officer
Moody, Sally Ann
Project Start
1997-12-22
Project End
2004-07-19
Budget Start
2004-06-01
Budget End
2004-07-19
Support Year
7
Fiscal Year
2004
Total Cost
$34,298
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Ching, Yung-Hao; Wilson, Lawriston A; Schimenti, John C (2010) An allele separating skeletal patterning and spermatogonial renewal functions of PLZF. BMC Dev Biol 10:33
Ching, Yung-Hao; Munroe, Robert J; Moran, Jennifer L et al. (2010) High resolution mapping and positional cloning of ENU-induced mutations in the Rw region of mouse chromosome 5. BMC Genet 11:106
Munroe, Robert J; Prabhu, Vinay; Acland, Greg M et al. (2009) Mouse H6 Homeobox 1 (Hmx1) mutations cause cranial abnormalities and reduced body mass. BMC Dev Biol 9:27
Mu, Weipeng; Wang, Wei; Schimenti, John C (2008) An allelic series uncovers novel roles of the BRCT domain-containing protein PTIP in mouse embryonic vascular development. Mol Cell Biol 28:6439-51
Harris, Tanya; Marquez, Becky; Suarez, Susan et al. (2007) Sperm motility defects and infertility in male mice with a mutation in Nsun7, a member of the Sun domain-containing family of putative RNA methyltransferases. Biol Reprod 77:376-82
Suarez, Susan S; Marquez, Becky; Harris, Tanya P et al. (2007) Different regulatory systems operate in the midpiece and principal piece of the mammalian sperm flagellum. Soc Reprod Fertil Suppl 65:331-4
Howell, Gareth R; Shindo, Mami; Murray, Stephen et al. (2007) Mutation of a ubiquitously expressed mouse transmembrane protein (Tapt1) causes specific skeletal homeotic transformations. Genetics 175:699-707
Wilson, Lawriston; Ching, Yung-Hao; Farias, Michael et al. (2005) Random mutagenesis of proximal mouse chromosome 5 uncovers predominantly embryonic lethal mutations. Genome Res 15:1095-105
Symula, Derek J; Zhu, Yiwen; Schimenti, John C et al. (2004) Functional annotation of mouse mutations in embryonic stem cells by use of expression profiling. Mamm Genome 15:1-13
Shima, Naoko; Hartford, Suzanne A; Duffy, Ted et al. (2003) Phenotype-based identification of mouse chromosome instability mutants. Genetics 163:1031-40

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