Roles for RERE in lymphatic endothelial cell proliferation and survival, and human cystic lymphatic malformations

Abstract

ABSTRACTHuman congenital lymphatic anomalies (LAs) arise due to defects in lymphatic development. During a genetic study of fetuses with LAs, we identified a heterozygous pathogenic truncating variant inREREin a fetus with a cystic lymphatic malformation (CLM). RERE is a transcriptional regulator which interacts with several key lymphangiogenic factors, including Notch and Coup-TFII. RERE also modulates retinoic acid signaling, which is essential for lymphatic vascular development. Thus, we hypothesized that RERE functions in lymphatic endothelial cells (LECs) and its loss contributes to LEC dysfunction and CLM pathogenesis. RERE was found to be expressed in the lymphatic endothelium during human development.REREknockdown in human LECs reduced proliferation and induced apoptosis, increased expression of key lymphangiogenic genes,PROX1, COUP-TFIIandVEGFR3, and altered expression of Notch target genes. RERE expression was elevated in LECs isolated from CLMs with pathogenicPIK3CAvariants. These findings support a novel role for RERE in LECs, where RERE regulates LEC proliferation, LEC survival, lymphangiogenic gene expression and Notch signaling, which in turn suggests its loss contributes to CLM pathogenesis.