Targeted deletion of the murine apobec-1 complementation factor (acf) gene results in embryonic lethality.
apobec-1 complementation factor (ACF) is an hnRNP family member which functions as the obligate RNA binding subunit of the core enzyme mediating C-to-U editing of the nuclear apolipoprotein B (apoB) transcript. ACF binds to both apoB RNA and apobec-1, the catalytic cytidine deaminase, which then results in site-specific posttranscriptional editing of apoB mRNA. Targeted deletion of apobec1 eliminates C-to-U editing of apoB mRNA but is otherwise well tolerated. However, the functions and potential targets of ACF beyond apoB mRNA editing are unknown. Here we report the results of generating acf knockout mice using homologous recombination. While heterozygous acf(+/)(-) mice were apparently healthy and fertile, no viable acf(-)(/)(-) mice were identified. Mutant acf(-)(/)(-) embryos were detectable only until the blastocyst (embryonic day 3.5 [E3.5]) stage. No acf(-)(/)(-) blastocysts were detectable following implantation at E4.5, and isolated acf(-)(/)(-) blastocysts failed to proliferate in vitro. Small interfering RNA knockdown of ACF in either rat (apobec-1-expressing) or human (apobec-1-deficient) hepatoma cells decreased ACF protein expression and induced a commensurate increase in apoptosis. Taken together, these data suggest that ACF plays a crucial role, which is independent of apobec-1 expression, in cell survival, particularly during early embryonic development.
Blanc
Valerie
V
Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Henderson
Jeffrey O
JO
Newberry
Elizabeth P
EP
Kennedy
Susan
S
Luo
Jianyang
J
Davidson
Nicholas O
NO
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D017209:Apoptosis; D003433:Crosses, Genetic; D003564:Cytidine Deaminase / Q000378:metabolism; D010064:Embryo Implantation; D005091:Exons; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005816:Genetic Complementation Test; D005822:Genetic Vectors; D005838:Genotype; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics* / Q000502:physiology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007438:Introns; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics*; D051381:Rats; D011995:Recombination, Genetic; D014158:Transcription, Genetic
C411647:A1CF protein, human; D001055:Apolipoproteins B; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C503503:apobec-1 complementation factor, mouse; D012313:RNA; D003564:Cytidine Deaminase