Developmental senescence misregulation in congenital disorders: CHARGE syndrome as a candidate model

Developmental senescence has recently emerged as a physiological program that contributes to tissue remodeling, morphogenesis and growth regulation during vertebrate embryogenesis. While transient and non-pathological under normal conditions, this program requires strict spatial and temporal control. Here we argue that its misregulation represents a source of congenital defects. In particular, we suggest that the deficiency of the chromatin remodeler CHD7, the major genetic cause of CHARGE syndrome, may disrupt the spatiotemporal boundaries of developmental senescence. This hypothesis is supported by several lines of evidence in vertebrate models: first, CHD7 expression domains during development largely overlap with regions where physiological embryonic senescence has been described. Second, CHD7 reduction is associated with altered cell proliferation and misregulation of key senescence-related pathways including those driven by p53, p21 and TGFβ. Disruption of this regulatory balance may alter the timing of cellular growth arrest, clearance and tissue differentiation, providing a plausible mechanistic framework for the multisystemic anomalies observed in CHARGE syndrome.