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LMBR1L regulates the proliferation and migration of endothelial cells through Norrin/β-catenin signaling.

Wenjing LiuXiaoyan JiangXiao LiKuanxiang SunYeming YangMu YangShujin LiXianjun Zhu
Published in: Journal of cell science (2022)
Precise Norrin and β-catenin (Norrin/β-catenin; encoded by NDP and CTNNB1, respectively) signaling is critical for proper angiogenesis. Dysregulation of this signaling leads to various diseases, of which retinal exudative vitreoretinopathy is the most prevalent. Here, we used a global knockout mouse model to show that limb development membrane protein 1 like (LMBR1L), a transmembrane protein of unknown function in angiogenesis, is essential for retinal vascular development. In vitro experiments revealed that LMBR1L depletion results in aberrant activation of the Norrin/β-catenin signaling pathway via decreased ubiquitylation of FZD4 and increased Norrin co-receptor LRP5 and p-GSK3β-Ser9 expression levels, which cause accumulation of β-catenin. Moreover, inhibition of LMBR1L in human retinal microvascular endothelial cells (HRECs) caused increased proliferation ability and defective cell migration, which might have occurred as a result of upregulated expression levels of the apical junction components. Treatment with p-GSK3β-Ser9 inhibitor AR-A014418 restored the phenotypes in LMBR1L-null HRECs, which further demonstrated the important regulatory role of LMBR1L in the Norrin/β-catenin signaling pathway. Taken together, our data reveal an essential role for LMBR1L in angiogenesis. This article has an associated First Person interview with the first author of the paper.
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