Prdm16 amplifies Notch signaling and suppresses venous lineage specification to prevent arteriovenous malformations during vascular development

Abstract

Proper arterial versus venous endothelial lineage identity is required to establish a hierarchical network of arteries and veins and prevent the occurrence of life-threatening arteriovenous malformations. The molecular mechanisms that govern arteriovenous lineage specification remain however incompletely understood. Here, we demonstrate that the transcription factor Prdm16 is expressed in arterial but not venous endothelial cells (ECs) from the earliest stages of development, where it actively promotes arterial EC identity by enhancing canonical Notch activity, while simultaneously suppressing the alternative venous cell fate. Concordantly, our results in zebrafish show that Prdm16 coordinates proper arterial development and arteriovenous lineage specification together with canonical Notch signaling, as combined loss of prdm16 and notch in zebrafish invariably leads to arteriovenous malformations (AVMs). Although the arterializing effect of Prdm16 in human ECs is dependent on the absolute levels of the cleaved intracellular domain of the Notch receptors (NICD), Prdm16 does not increase NICD levels per se. Rather, Prdm16 physically and functionally interacts with NICD to potentiate its effect. Prdm16 further finetunes Notch signaling and arterial development by complexing with the Notch downstream effector Hey2, which regulates arterial lineage specification and development across species. Together, our data demonstrate that Prdm16 act as a rheostat for endothelial Notch activity and suggest that Prdm16 signaling may constitute a novel therapeutic target for AVMs.