Akt is a mediator of artery specification during zebrafish development.
Wenping Zhou, Joey J Ghersi, Emma Ristori, Nicole Semanchik, Andrew Prendergast, Rong Zhang, Paola Carneiro, Gabriel Baldissera, William C Sessa, Stefania Nicoli
Author Information
Wenping Zhou: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
Joey J Ghersi: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA. ORCID
Emma Ristori: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
Nicole Semanchik: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
Andrew Prendergast: Department of Comparative Medicine, Yale zebrafish Research Core, Yale University School of Medicine, New Haven, CT 06510, USA.
Rong Zhang: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
Paola Carneiro: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
Gabriel Baldissera: Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale University School of Medicine, New Haven, CT 06511, USA.
William C Sessa: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
Stefania Nicoli: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA. ORCID
The dorsal aorta (DA) is the first major blood vessel to develop in the embryonic cardiovascular system. Its formation is governed by a coordinated process involving the migration, specification, and arrangement of angioblasts into arterial and venous lineages, a process conserved across species. Although vascular endothelial growth factor a (VEGF-A) is known to drive DA specification and formation, the kinases involved in this process remain ambiguous. Thus, we investigated the role of protein kinase B (Akt) in zebrafish by generating a quadruple mutant (aktΔ/Δ), in which expression and activity of all Akt genes - akt1, -2, -3a and -3b - are strongly decreased. Live imaging of developing aktΔ/Δ DA uncovers early arteriovenous malformations. Single-cell RNA-sequencing analysis of aktΔ/Δ endothelial cells corroborates the impairment of arterial, yet not venous, cell specification. Notably, endothelial specific expression of ligand-independent activation of Notch or constitutively active Akt1 were sufficient to re-establish normal arterial specification in aktΔ/Δ. The Akt loss-of-function mutant unveils that Akt kinase can act upstream of Notch in arterial endothelial cells, and is involved in proper embryonic artery specification. This sheds light on cardiovascular development, revealing a mechanism behind congenital malformations.
