Genetic variation in the anaphase promoting complex modulates fertility and chromosome alignment defects in the absence of KIF18A
The kinesin family member 18A (Kif18a) is an essential regulator of microtubule dynamics and chromosome alignment during mitosis. Laboratory mice with a loss of function mutation in Kif18a are are infertile due to mitotic arrest of germ cells, but this phenotype shows variable penetrance depending on genetic background. Kif18a is also necessary for mitotic progression of chromosomally unstable cancer cells, which exhibit mitotic arrest in the absence of KIF18A function. While it is clear that functional dependency on KIF18A varies by cell type and genetic context, the heritable factors that influence this dependency remain unknown. To address this, we took advantage of the variable penetrance observed in different mouse strain backgrounds to screen for genetic loci that modulate germ cell depletion in the absence of KIF18A. We found a significant association between the severity of germ cell depletion and a locus on Chr5 wherein anaphase promoting complex subunits 5 (Anapc5) and 7 (Anapc7) were the top candidate genes. We compared the expression of both genes at key timepoints in gondal development and found that both genes were differentially expressed in sensitive strain backgrounds when compared to resistant strain backgrounds. We also identify a novel retroviral insertion in Anapc7 that may in part explain the observed expression differences. In cell line models, we found that depletion of KIF18A induced mitotic arrest, which was partially rescued by co-depletion of APC7 and exacerbated by co-depletion of APC5. These findings suggest that differential expression and activity of Anapc5 and Anapc7 may influence sensitivity to KIF18A depletion in germ cells and CIN cells, with potential implications for optimizing antineoplastic therapies. Overall design: We generated RNASeq data from testes and ovaries to evaluate the developmental and tissue specific expression profiles of the genes in the Chr5 QTL. Five biological replicates were collected from each sex (male, female), strain (C57BL/6J, CAST/EiJ, and B6CastF1), developmental timepoint~sex (ovaries at 12.5-13.5 days post coitum, testes at 5 days post partum). These developmental timepoints were chosen because mitotically dividing germ cells are enriched. In GEO metadata strain is designated under "genotype" as B6 (C57BL/6J: RRID:IMSR_JAX:000664), CAST (CAST/EiJ: RRID:IMSR_JAX:000928), and F1 offspring 'B6Cast' from a cross between B6 female x CAST male (C57BL/6J x CAST/EiJ F1).