Programmed senescence plays an important role in adult tissue homeostasis and has recently been shown to occur as part of some normal developmental processes, including inner ear morphogenesis. However, it is unclear whether the perturbation of developmental senescence can result in congenital defects. Ignacio Palmero and colleagues have previously shown that SIX1 negatively regulates adult cell senescence, and this protein has also been implicated in human BOR syndrome, a disease affecting ear, kidney and branchial arch morphology. Here, they confirm that Six1-deficient mouse embryos exhibit abnormal inner ear morphology and show that the senescent regions of this tissue are expanded in comparison with wild-type embryos. RNA-sequencing shows that depletion of Six1 leads to reduced expression of cell cycle and DNA replication genes, and increased expression of genes involved in protein secretion and lysosomal activity, which are consistent with increased senescence. The expression of TGFβ signalling components is also disrupted, and the authors find that inhibiting BMP signalling partially rescues the abnormal gene expression profile of the Six1-deficient vesicles. They are also able to recapitulate the Six1-deficient phenotype in wild-type otic vesicles by pharmacologically inducing senescence ex vivo. Together, these results demonstrate that dysregulated developmental senescence could contribute to congenital disease.
Aberrant senescence in congenital disease
Aberrant senescence in congenital disease. Development 1 May 2023; 150 (9): e150_e0901. doi:
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