Format

Send to

Choose Destination
Nat Commun. 2019 Jun 13;10(1):2588. doi: 10.1038/s41467-019-10411-w.

Robust elimination of genome-damaged cells safeguards against brain somatic aneuploidy following Knl1 deletion.

Shi L1,2, Qalieh A1,2, Lam MM1,2, Keil JM1,2,3, Kwan KY4,5.

Author information

1
Molecular & Behavioral Neuroscience Institute (MBNI), University of Michigan, Ann Arbor, MI, 48109, USA.
2
Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
3
Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, 48109, USA.
4
Molecular & Behavioral Neuroscience Institute (MBNI), University of Michigan, Ann Arbor, MI, 48109, USA. kykwan@umich.edu.
5
Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA. kykwan@umich.edu.

Abstract

The brain is a genomic mosaic shaped by cellular responses to genome damage. Here, we manipulate somatic genome stability by conditional Knl1 deletion from embryonic mouse brain. KNL1 mutations cause microcephaly and KNL1 mediates the spindle assembly checkpoint, a safeguard against chromosome missegregation and aneuploidy. We find that following Knl1 deletion, segregation errors in mitotic neural progenitor cells give rise to DNA damage on the missegregated chromosomes. This triggers rapid p53 activation and robust apoptotic and microglial phagocytic responses that extensively eliminate cells with somatic genome damage, thus causing microcephaly. By leaving only karyotypically normal progenitors to continue dividing, these mechanisms provide a second safeguard against brain somatic aneuploidy. Without Knl1 or p53-dependent safeguards, genome-damaged cells are not cleared, alleviating microcephaly, but paradoxically leading to total pre-weaning lethality. Thus, mitotic genome damage activates robust responses to eliminate somatic mutant cells, which if left unpurged, can impact brain and organismal fitness.

PMID:
31197172
PMCID:
PMC6565622
DOI:
10.1038/s41467-019-10411-w
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center