X chromosome dosage in respiratory stem cells is critical for post-embryonic development and survival

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.