X chromosome dosage in respiratory stem cells is critical for post-embryonic development and survival
Year: 2025
Type: article
Abstract: Sex chromosome pairs, while carrying sex-determining genes, often exhibit marked structural heteromorphism due to extensive gene loss on the sex-specific chromosome. This heteromorphism generates a fundamental dosage imbalance in sex-linked gene expression, with one sex having one copy and the other two. To address this imbalance and equalize gene expression between the sexes, many species have evolved epigenetic-based, chromosome-wide dosage compensation (DC) mechanisms. While the molecular machinery governing such processes is well characterized in model organisms, the cause of sex-specific lethality due to compensation failure or naturally occurring X monosomy remains unknown. Here, we innovated Drosophila melanogaster genetic tools to investigate X chromosome DC in somatic organs. By implementing ∼150 cell-type-specific perturbations across developmental stages, we uncover cell populations requiring X chromosome DC for sex-specific survival to adulthood. Unexpectedly, DC is largely dispensable across many tissues and developmental stages, with the exception, among others, of the respiratory system during metamorphosis, where X chromosome DC determines adult stem cell viability. Furthermore, we demonstrate that cellular polyploidy confers insensitivity to X-dosage perturbations, providing a mechanistic explanation for cell-type-specific dispensability of DC. These findings reveal how X aneuploidy impairs development and highlight the initial cellular events leading to organismal death.
Source: Current Biology
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $7,030
Funders: European Molecular Biology Organization, Wellcome Trust, Francis Crick Institute, Cancer Research UK, Agence Nationale de la Recherche, EMBO, HORIZON EUROPE Framework Programme, Medical Research Council, Engineering and Physical Sciences Research Council, European Research Council, H2020 European Research Council
OpenAlex ID: W7116663159