BioProject

The brain is a genomic mosaic shaped by cellular responses to genome damage. More...

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. Overall design: We sequenced a total of 16 samples of rRNA-depleted RNA from E15.5 mouse cerebral cortex. A total of 15 mice were used and 16 UMI RNA-seq libraries were generated. 7 samples were controls (wild type or heterozygote), 5 samples were hGFAP-Cre Knl1 (Casc5) conditional KO, and 4 samples were hGFAP-Cre Knl1/Trp53 double conditional KO. Less...