Pluto Bioinformatics

GSE114956: Robust apoptotic and microglial responses to brain somatic genome damage following Casc5 deletion

Bulk RNA sequencing

The brain is a genomic mosaic. Here, we manipulated somatic genome stability by conditional Casc5 deletion from embryonic mouse brain and studied the in vivo consequences. CASC5 (KNL1) mutation is a cause of human microcephaly and CASC5 mediates the spindle assembly checkpoint, disruption of which causes chromosome missegregation and aneuploidy. We found that following Casc5 deletion, segregation errors in mitotic neural progenitor cells gave rise to missegregated chromosomes and micronuclei with DNA damage, which triggered robust p53 target gene activation likely independently of aneuploidy. Widespread apoptosis rapidly followed, leading to significant cell loss and severe microcephaly. Co-deletion of Trp53 with Casc5, however, only partially rescued these phenotypes; chromosome damage elicited apoptosis even in the absence of p53. Finally, we found that genome-damaged cells were rapidly eliminated by activated microglia via phagocytosis. Our work thus revealed robust responses to somatic genome damage and their potential to limiting deleterious brain somatic mutations. SOURCE: Kenneth,Y,Kwan (kykwan@umich.edu) - University of Michigan