Acute systemic loss of Mad2 leads to intestinal atrophy in adult mice

Abstract

Chromosomal instability (CIN) is a hallmark of cancer, leading to aneuploid cells. To study the role that CIN plays in tumor evolution, several mouse models have been engineered over the last 2 decades. These models have unequivocally shown that systemic high-grade CIN is embryonic lethal. We and others have previously shown that embryonic lethality can be circumvented by provoking CIN in a tissue-specific fashion. In this study, we provoke systemic high-grade CIN in adult mice as an alternative to circumvent embryonic lethality. For this, we disrupt the spindle assembly checkpoint (SAC) by alleviating Mad2 or truncating Mps1, both essential genes for SAC functioning, with or without p53 inactivation. We find that disruption of the SAC leads to rapid villous atrophy, atypia and apoptosis of the epithelia of the jejunum and ileum, substantial weight loss, and death within 2–3 weeks after the start of the CIN insult. Despite this severe intestinal phenotype, most other tissues are unaffected, except for minor abnormalities in spleen, presumably due to the lower proliferation rate in these tissues. We conclude that high-grade CIN in vivo in adult mice is most toxic to the high cell turnover intestinal epithelia.

Chronic deregulation of the spindle assembly checkpoint triggers myelosuppression and gastrointestinal atrophy

“…Consistently, gastrointestinal stem cells and the transient amplifying pool seemed to be the most affected cells by MAD2 overexpression and extended mitosis as an imbalance in MAD2 expression in either direction can cause prolonged SAC activation 27, 29 . Our finding is well in line with a recent report showing that timed conditional deletion of MAD2 in Mad2l1 f/f mice carrying a CRE ERT2 transgene triggers a similar phenotype with rapid weight loss, mitotic abnormalities and increased apoptosis in intestinal crypts, causing rapid animal death 63 .…”

Chronic spindle assembly checkpoint activation causes myelosuppression and gastrointestinal atrophy

“…Consistently, gastrointestinal stem cells and the transient amplifying pool seemed to be the most affected cells by MAD2 overexpression and extended mitosis as an imbalance in MAD2 expression in either direction can cause prolonged SAC activation (Michel et al, 2001 ; Sotillo et al, 2007 ). Our finding is well in line with a recent report showing that timed conditional deletion of MAD2 in Mad2l1 f/f mice carrying a CRE ERT2 transgene triggers a similar phenotype with rapid weight loss, mitotic abnormalities and increased apoptosis in intestinal crypts, causing rapid animal death (Schukken et al, 2021 ).…”

Mitotic checkpoint gene expression is tuned by codon usage bias

“…Mouse models have shown that impairing the SAC promotes chromosome mis‐segregation and tumor formation (Baker et al , 2005 ; Holland & Cleveland, 2009 ; Schvartzman et al , 2010 ). Completely abolishing the SAC, however, is detrimental to human cells (Dobles et al , 2000 ; Kops et al , 2004 ; Michel et al , 2004 ; Schukken et al , 2021 ), and suppression of the SAC may in fact be a successful therapeutic strategy against some cancer types (Cohen‐Sharir et al , 2021 ; Quinton et al , 2021 ). Together, these results indicate that tuning SAC function can make the difference between normal growth, cancerous growth, and cell death.…”