Dysfunction of programmed embryo senescence is linked to genetic developmental defects

Abstract

Developmental senescence is a form of programmed senescence that contributes to morphogenesis during embryonic development. We showed recently that the SIX1 homeoprotein, an essential regulator of organogenesis, is also a repressor of adult cellular senescence. Alterations in the SIX/EYA pathway are linked to the human Branchio-Oto-Renal (BOR) syndrome, a rare congenital disorder with defects in the ear, kidney and branchial arches. Here, we have used Six1-deficient mice, an animal model of the BOR syndrome, to investigate whether dysfunction of senescence underpins the developmental defects associated with SIX1 deficiency. We have focused on the developing inner ear, an organ with physiological developmental senescence that is severely affected in Six1-deficient mice and BOR patients. We show aberrant levels and distribution of senescence markers in Six1-deficient inner ears concomitant with defective morphogenesis of senescent structures. Transcriptomic analysis and ex vivo assays support a link between aberrant senescence and altered morphogenesis in this model, associated to the deregulation of the TGF-beta/BMP pathway. Our results show that misregulation of embryo senescence may lead to genetic developmental disorders, significantly expanding the connection between senescence and disease.

GDF‐15 is associated with sarcopenia and frailty in acutely admitted older medical patients

“…9 This is supported by the fact that active individuals have lower resting levels of GDF-15 compared with sedentary individuals. 8 Notably, although senescence plays a key role in wound repair, embryogenesis, and development processes, [10][11][12] chronically elevated levels of systemic senescence as observed with ageing or various disease states is likely detrimental. 9 We have previously reported increases in systemic GDF-15 with age in healthy men and women and a negative relationship between circulating GDF-15 levels and relative muscle power, 13 supporting the evidence of increased senescence with age and a potential effect on muscle performance.…”

“… 9 This is supported by the fact that active individuals have lower resting levels of GDF‐15 compared with sedentary individuals. 8 Notably, although senescence plays a key role in wound repair, embryogenesis, and development processes, 10 , 11 , 12 chronically elevated levels of systemic senescence as observed with ageing or various disease states is likely detrimental. 9 …”