Genomes and Genes
Genome-wide ENU mutagenesis screen for Runx2 modifiers
Principal Investigator: PATRICIA FLORENCE DUCY
Abstract: The long-term goal of our project is to identify factors regulating mesenchymal cells commitment and early maturation into differentiated osteoblasts. As a first step toward this goal, we propose to perform a genome-wide genetic screen in mice using ethyl-nitrosourea (ENU) mutagenesis to expose mutations able to functionally compensate for Runx2 haploinsufficiency. Runx2 is the earliest known determinant of osteoblast differentiation, and loss of one Runx2 allele in mice or human causes Cleidocranial dysplasia (CCD), a skeletal disorder marked by clavicle agenesis and ossification defects. Any regulator of Runx2 expression or activity is thus likely to be involved in controlling either osteoblast differentiation or osteoblast function. Our strategy relies on a search for ENU-mutated animals that harbor a rescued CCD phenotype despite a Runx2 genetic background. We hypothesize that such rescuing mutations will affect regulators of Runx2 gene expression or protein stability/availability/activity or trigger yet unknown parallel or downstream compensating pathways. Subsequent characterization of the genes harboring these mutations should thus identify regulators involved in the early steps of skeletogenesis. The present application proposes to identify rescued Runx2 ENU mutants and to select the best candidates for subsequent mutation mapping and gene identification. Our specific aims are: to identify ENU-mutated mouse strains harboring a rescue of the CCD phenotype despite heterozygocity at the Runx2 locus; and to compare the mutant lines isolated and prioritize them for subsequent mutation mapping.
Funding Period: 2005-08-01 - 2008-07-31
more information: NIH RePORT
- Microarray analysis on Runx2-deficient mouse embryos reveals novel Runx2 functions and target genes during intramembranous and endochondral bone formationBart L T Vaes
Department of Applied Biology FNWI, Radboud University Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Bone 39:724-38. 2006..In conclusion, our data show that a comparative genome-wide expression analysis of wild-type and mutant mouse models allows the examination of mutant phenotypes in complex tissues...