Net-targeted mutant mice develop a vascular phenotype and up-regulate egr-1

The ternary complex factors (TCFs) Net, Elk-1 and Sap-1 regulate immediate early genes through serum response elements (SREs) in vitro, but, surprisin gly, their in vivo roles are unknown. Net is a repressor that is expressed in sites of vasculogenesis during mouse development. We have made gene-targ eted mice that express a hypomorphic mutant of Net, Net delta, which lacks the Ets DNA-binding domain. Strikingly, homozygous mutant mice develop a va scular defect and up-regulate an immediate early gene implicated in vascula r disease, egr-1. They die after birth due to respiratory failure, resultin g from the accumulation of chyle in the thoracic cage (chylothorax). The mi ce have dilated lymphatic vessels (lymphangiectasis) as early as E16.5. Int erestingly, they express more egr-1 in heart and pulmonary arteries at E18. 5. Net negatively regulates the egr-1 promoter and binds specifically to SR E-5. Egr-1 has been associated with pathologies involving vascular stenosis (e.g. atherosclerosis), and here egr-1 dysfunction could possibly be assoc iated with obstructions that ultimately affect the lymphatics. These result s show that Net is involved in vascular biology and egr-1 regulation in viv o.