Asymmetric chromatin capture and nuclear envelopes separate chromosomes in fused cells during mitosis

Hybrid cells derived through fertilization or somatic cell fusion recognize and separate chromosomes of different origin. The underlying mechanisms are unknown but could prevent aneuploidy and tumor formation. Here, we acutely induce fusion between Drosophila neural stem cells (neuroblasts; Nbs) and differentiating ganglion mother cells (GMCs) in vivo to define how epigenetically distinct chromatin is recognized and segregated. We find that Nb-GMC hybrid cells align both endogenous (neuroblast-origin) and ectopic (GMC-origin) chromosomes at the metaphase plate through centrosome derived dual-spindles. Mixing of endogenous and ectopic chromatin is prevented through an asymmetric, microtubule-dependent chromatin capture mechanism during interphase and physical boundaries imposed by nuclear envelopes. Although hybrid cells fail to accurately segregate ectopic chromatin, hybrid cells neither reduce the lifespan nor form visible tumors in host flies. We propose that Nb-GMC derived hybrid cells utilize asymmetric centrosome activity in interphase and nuclear envelopes to physically separate epigenetically distinct chromatin.