Lamin A/C Maintains Exocrine Pancreas Homeostasis by Regulating Stability of RB and Activity of E2F

Lamins have important roles in nuclear structure and cell signaling. Several diseases are associated with mutations in the lamin A/C gene (LMNA in humans). Patients with familial partial lipodystrophy caused by LMNA mutations develop pancreatitis, but lamin function in the pancreas and how these mutations affect pancreatic regulation are unknown. We generated mice with inducible exocrine pancreas-specific disruption of Lmna and showed that LMNA is lost from most exocrine pancreas cells. LMNAknockout pancreata develop endoplasmic reticulum stress with loss of acinar cell markers, increased autophagy, apoptosis, and cell proliferation, compared to CreERT2(-) mice (littermate controls). Disruption of Lmna led to a phenotype that resembled chronic pancreatitis, with increased Sirius Red staining and alpha-smooth muscle actin in male LMNA-knockout mice compared to littermate males, but not in female mice. LMNA-knockout pancreata have reduced levels of RB and activation of E2F, based on increased expression of E2F target genes. Therefore, lamins maintain pancreatic homeostasis by regulating RB stability and E2F activity.