ELAVL1 regulates alternative splicing of eIF4E transporter to promote postnatal angiogenesis

Posttranscriptional RNA regulation is important in determining the plasticity of cellular phenotypes. However, mechanisms of how RNA binding proteins (RBPs) influence cellular behavior are poorly understood. We show here that the RBP embryonic lethal abnormal vision like 1 (ELAVL1, also know as HuR) regulates the alternative splicing of eukaryotic translation initiation factor 4E nuclear import factor 1 ( Eif4enif1 ), which encodes an eukaryotic translation initiation factor 4E transporter (4E-T) protein and suppresses the expression of capped mRNAs. In the absence of ELAVL1, skipping of exon 11 of Eif4enif1 forms the stable, short isoform, 4E-T ₛ. This alternative splicing event results in the formation of RNA processing bodies (PBs), enhanced turnover of angiogenic mRNAs, and suppressed sprouting behavior of vascular endothelial cells. Further, endothelial-specific Elavl1 knockout mice exhibited reduced revascularization after hind limb ischemia and tumor angiogenesis in oncogene-induced mammary cancer, resulting in attenuated blood flow and tumor growth, respectively. ELAVL1-regulated alternative splicing of Eif4enif1 leading to enhanced formation of PB and mRNA turnover constitutes a novel posttranscriptional mechanism critical for pathological angiogenesis. Significance Angiogenesis, or new blood vessel formation, is critical not only for normal processes such as embryonic development but also for progression of diseases such as tumor growth, metastasis, and chronic inflammatory disease. This work elucidated a molecular mechanism that is important in postnatal angiogenesis in tumor growth and ischemia–reperfusion injury in the hind limb. Specifically, we identified a posttranscriptional gene regulatory mechanism that controls the activity of a potent suppressor of gene expression, named eIF4e transporter (4E-T). Alternative splicing of 4E-T controls the level of the active form of 4E-T, which suppresses gene expression in endothelial cells. This mechanism may be targeted to control angiogenesis-dependent diseases.