Requirement of GCN5 histone acetyltransferase in mouse skeletal patterning and neural tube closure

Disruption of the gene that encodes the HAT GCN5 leads to embryonic lethality at 10.5 d.p.c. To address GCN5 functions at later developmental stages or in specific tissue differentiation, we created a conditional GCN5 allele in which a key portion of the coding sequence is flanked by site‐specific loxP recombination sites. The floxed sequence can be removed at specific developmental stages or tissues after introducing Cre recombinase. The phenotype of the embryo will help us to define GCN5 functions at specific embryonic time points and in specific tissues. Two ES cell heterozygous clones 2G2 and 2D10 which carry the conditional GCN5 allele have been injected into blastocysts to generate chimeric mice and germline transmission GCN5 flox(neo)/+ mice have been screened from both clone 2G2 and clone 2D10, respectively. Genetic data indicate that the neomycin cassette which is inserted into the second intron of GCN5 causes a hypomorphic mutation. This mutation provides us a new model to investigate GCN5 functions in murine embryogenesis. Preliminary data show that there are anterior homeotic transformation and exencephaly phenotypes in both GCN5 flox(neo)/flox(neo) embryos and GCN5 flox(neo)/− embryos. All GCN5 flox(neo)/ − embryos have anterior homeotic transformation while just a fraction of GCN5 flox(neo)/flox(neo) embryos have this phenotype. some GCN5 flox(neo)/flox(neo) embryos and GCN5 flox(neo)/ − embryos exhibit an exencephaly phenotype due to an early neural tube closure defect. Taken together, these data suggest that GCN5 plays an important role in anterior‐posterior patterning and neural tube closure in a dose dependent manner.