Loss of Borealin/DasraB leads to defective cell proliferation, p53 accumulation and early embryonic lethality

Abstract

Borealin/DasraB is a member of the chromosomal passenger protein complex (CPC) required for proper segregation of chromosomes during mitosis. In Drosophila melanogaster, inactivation of Borealin/DasraB results in polyploidy, delayed mitosis and abnormal tissue development, indicating its critical role for cell proliferation. However, the in vivo role of mammalian Borealin/DasraB remains unclear. Here, we analyzed the expression of Borealin/DasraB and found that borealin is widely expressed in embryonic tissues and later restricted to adult tissues which relies on rapid cell proliferation. To determine the role of borealin during mouse development, we generated borealin-null mice through targeted disruption. While heterozygous mice developed normally, disruption of both borealin alleles resulted in early embryonic lethality by 5.5 dpc (days postcoitus) due to mitotic defects and apoptosis in blastocyst cells that showed microtubule disorganization and no CPC enrichment. At 5.5 dpc, borealin-null embryos exhibited excessive apoptosis and elevated expression of p53. However, loss of p53 did not abrogate or delay embryonic lethality, revealing that Borealin/DasraB inactivation triggered impaired mitosis and apoptosis though p53-independent mechanisms. Our data show that Borealin/DasraB is essential for cell proliferation during early embryonic development, and its early embryonic lethality cannot be rescued by the loss of p53.

Aurora B Is Regulated by the Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase (MAPK/ERK) Signaling Pathway and Is a Valuable Potential Target in Melanoma Cells

“…Aurora B functions in complex with Survivin, Borealin, and INCENP allowing the docking of Aurora B at the right place at the right time during mitosis (30). Depletion of any one subunit of the Aurora B-INCENP-Borealin-Survivin complex caused a substantial reduction not only in the corresponding target but also in the other subunits and may promote cell death (31,32). Therefore, by using AZD1152, several actors and tumor signaling circuitries may be simultaneously disabled, amplifying the anti-tumor effect of the Aurora B inhibitor.…”

Genetic disruption of aurora B uncovers an essential role for aurora C during early mammalian development

“…However, its relevance in CPC function and mitosis in vivo has not been elucidated given the reduced endogenous expression levels in cultured cell lines. The fact that aurora B-null embryos survive up to postimplantation stages is certainly surprising given the earlier lethality of incenp, survivin or borealin-deficient embryos (Cutts et al, 1999;Uren et al, 2000;Yamanaka et al, 2008) and the crucial roles of the CPC in cell division. During pre-implantation, incenp is properly located in the absence of aurora B and the phenotypes expected from perturbed CPC function are not observed.…”

“…No homozygous mutant was born and no homozygous embryos were observed at 2663 RESEARCH ARTICLE Cellular requirements for aurora B and C in mammals mid gestation, suggesting early embryonic lethality (see Table S1 in the supplementary material). Because genetic ablation of the other CPC components, incenp, borealin or survivin, prevents embryonic cell divisions as early as E2.5 (Cutts et al, 1999;Uren et al, 2000;Yamanaka et al, 2008), we decided to isolate fertilized embryos at E2.0. By this stage, most embryos were at the 4-cell stage ( Fig.…”

“…S8 in the supplementary material). Aurora C is sufficient to drive mitotic progression during early embryonic development As lack of the other CPC components, incenp, survivin or borealin, results in early lethality by E2.5 (Cutts et al, 1999;Uren et al, 2000;Yamanaka et al, 2008), we wondered whether aurora B could be dispensable owing to the presence of other aurora kinases during early embryonic development. Indeed, aurora C has been shown previously to bind other CPC components when overexpressed in specific cell lines (Sasai et al, 2004;Slattery et al, 2009;Slattery et al, 2008;Yan et al, 2005).…”

“…In mammals, the CPC seems to be required for early embryonic development and embryos degenerate by E2.5-3.5 in the absence of the CPC components survivin (Uren et al, 2000), incenp (Cutts et al, 1999) or borealin (Yamanaka et al, 2008). We report here that aurora B-null embryos develop normally during the early cell divisions and die only after implantation, suggesting the presence of normal cell cycles in the early embryonic cell divisions in the absence of aurora B. Interestingly, aurora C is highly expressed during the early cell divisions and it seems to be responsible for CPC function in these pre-implantation embryos.…”