Mitotic chromosome alignment is required for proper nuclear envelope reassembly

Abstract

SUMMARYChromosome alignment at the equator of the mitotic spindle is a highly conserved step during cell division, however, its importance to genomic stability and cellular fitness are not understood. Normal mammalian somatic cells lacking Kif18A function complete cell division without aligning chromosomes. These alignment-deficient cells display normal chromosome copy numbers in vitro and in vivo, suggesting that chromosome alignment is largely dispensable for maintenance of euploidy. However, we find that loss of chromosome alignment leads to interchromosomal compaction defects during anaphase, abnormal organization of chromosomes into a single nucleus at mitotic exit, and the formation of micronuclei in vitro and in vivo. These defects slow cell proliferation and reduce postnatal growth and survival with variable penetrance in mice. Our studies support a model in which the alignment of mitotic chromosomes promotes proper nuclear envelope reassembly and continued proliferation by ensuring that chromosomes segregate as a compact mass during anaphase.

Micronuclei in Kif18a mutant mice form stable micronuclear envelopes and do not promote tumorigenesis

“…Mice homozygous for the Kif18a mutation germ cell depletion 2 ( gcd2 ) lack KIF18A activity and form micronuclei due to chromosome alignment defects in vivo ( Czechanski et al, 2015 ; Fonseca et al, 2019 ). While Kif18a gcd2/gcd2 mice are infertile due to mitotic defects during embryonic germline development, they do not develop spontaneous tumors ( Czechanski et al, 2015 ).…”

“…Recently, micronuclei were demonstrated to form as a result of chromosome alignment defects and asynchronous segregation during mitosis ( Fonseca et al, 2019 ). In cells lacking the function of the kinesin KIF18A, chromosomes fail to properly align at the mitotic spindle equator, segregate in a disordered fashion, and display an increased probability of forming micronuclei ( Fonseca et al, 2019 ).…”

“…Recently, micronuclei were demonstrated to form as a result of chromosome alignment defects and asynchronous segregation during mitosis ( Fonseca et al, 2019 ). In cells lacking the function of the kinesin KIF18A, chromosomes fail to properly align at the mitotic spindle equator, segregate in a disordered fashion, and display an increased probability of forming micronuclei ( Fonseca et al, 2019 ). Furthermore, mice with inactivating mutations in Kif18a form micronuclei in vivo , with micronuclear incidence significantly elevated from levels of spontaneously occurring micronuclei in WT mice.…”

“…These results raise questions about the conditions under which micronuclei might induce genomic instability and tumorigenesis in vivo . Kif18a mutant mice are a useful system for studying the effects of micronuclei in vivo since the level of aneuploidy observed in these mice is low, allowing separation of effects due to micronucleation from those caused by widespread aneuploidy ( Czechanski et al, 2015 ; Fonseca et al, 2019 ).…”

“…It is possible that micronuclei in Kif18a mutant mice minimally impact genomic stability due to p53-dependent cell-cycle arrest or maintenance of micronuclear envelope stability. Activation of p53 in micronucleated cells has been observed to cause cell-cycle arrest in the subsequent G1 phase ( Uetake and Sluder, 2010 ; Santaguida et al, 2017 ; Thompson and Compton, 2010 ), and micronucleated KIF18A knockout (KO) cells are subject to a p53-dependent cell-cycle arrest in culture ( Fonseca et al, 2019 ). It is plausible, then, that micronuclei produced due to loss of Kif18a do not contribute to tumorigenesis in mice because a p53-dependent pathway prevents micronucleated cells from dividing further.…”