Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Van Wauwe, Jore ; Craps, Sander ; Ashmita, KC ; Asuncion, Lisabel ; Vrancaert, Pieter ; Daems, Margo ; Finck, Chris ; Wright, Shane ; Müller, Christian and Leigh, Nicholas D. LU orcid , et al. (2024)
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Working paper/Preprint
publication status
published
subject
DOI
10.1101/2021.12.05.471275
language
English
LU publication?
yes
id
7bfcc1d4-f2ac-40d4-a941-e76cb0840e09
date added to LUP
2025-10-20 12:52:38
date last changed
2025-10-20 12:52:38
@misc{7bfcc1d4-f2ac-40d4-a941-e76cb0840e09,
  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.}},
  author       = {{Van Wauwe, Jore and Craps, Sander and Ashmita, KC and Asuncion, Lisabel and Vrancaert, Pieter and Daems, Margo and Finck, Chris and Wright, Shane and Müller, Christian and Leigh, Nicholas D. and Frye, Maike and MacRae, Calum A. and Luttun, Aernout and Beerens, Manu}},
  language     = {{eng}},
  month        = {{06}},
  note         = {{Preprint}},
  title        = {{Prdm16 amplifies Notch signaling and suppresses venous lineage specification to prevent arteriovenous malformations during vascular development}},
  url          = {{http://dx.doi.org/10.1101/2021.12.05.471275}},
  doi          = {{10.1101/2021.12.05.471275}},
  year         = {{2024}},
}