Centromere protein A (Cenpa for mouse, CENP-A for other species) is a histone 
H3-like protein that is thought to be involved in the nucleosomal packaging of 
centromeric DNA. Using gene targeting, we have disrupted the mouse Cenpa gene 
and demonstrated that the gene is essential. Heterozygous mice are healthy and 
fertile whereas null mutants fail to survive beyond 6.5 days postconception. 
Affected embryos show severe mitotic problems, including micronuclei and 
macronuclei formation, nuclear bridging and blebbing, and chromatin 
fragmentation and hypercondensation. Immunofluorescence analysis of interphase 
cells at day 5.5 reveals complete Cenpa depletion, diffuse Cenpb foci, absence 
of discrete Cenpc signal on centromeres, and dispersion of Cenpb and Cenpc 
throughout the nucleus. These results suggest that Cenpa is essential for 
kinetochore targeting of Cenpc and plays an early role in organizing centromeric 
chromatin at interphase. The evidence is consistent with the proposal of a 
critical epigenetic function for CENP-A in marking a chromosomal region for 
centromere formation.