Functional Coupling between the Extracellular Matrix and Nuclear Lamina by Wnt Signaling in Progeria

SummaryThe segmental premature aging disease Hutchinson-Gilford Progeria (HGPS) is caused by a truncated and farnesylated form of Lamin A. In a mouse model for HGPS, a similar Lamin A variant causes the proliferative arrest and death of postnatal, but not embryonic, fibroblasts. Arrest is due to an inability to produce a functional extracellular matrix (ECM), because growth on normal ECM rescues proliferation. The defects are associated with inhibition of canonical Wnt signaling, due to reduced nuclear localization and transcriptional activity of Lef1, but not Tcf4, in both mouse and human progeric cells. Defective Wnt signaling, affecting ECM synthesis, may be critical to the etiology of HGPS because mice exhibit skeletal defects and apoptosis in major blood vessels proximal to the heart. These results establish a functional link between the nuclear envelope/lamina and the cell surface/ECM and may provide insights into the role of Wnt signaling and the ECM in aging.

► Postnatal, but not fetal, cell growth is inhibited by a mutant farnesylated lamin A
► Wnt signaling, particularly Lef1, is reduced in Progeric human and mouse cells
► Downstream defects in extracellular matrix synthesis inhibit cell proliferation
► Mutant mice die early, exhibiting skeletal and vascular smooth muscle defects