淋巴管内皮
淋巴系统
生物
淋巴管新生
基因敲除
发病机制
癌症研究
细胞生物学
病理
免疫学
细胞凋亡
遗传学
医学
癌症
转移
作者
Daniella Rogerson,Ajit Muley,Zoe Vogel,Jessica L. Giordano,Ronald J. Wapner,Carrie J. Shawber
标识
DOI:10.1101/2024.03.24.586490
摘要
ABSTRACT Human 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 in RERE in 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. RERE knockdown in human LECs reduced proliferation and induced apoptosis, increased expression of key lymphangiogenic genes, PROX1, COUP-TFII and VEGFR3 , and altered expression of Notch target genes. RERE expression was elevated in LECs isolated from CLMs with pathogenic PIK3CA variants. 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.
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