Strong as a Hippo’s Heart: Biomechanical Hippo Signaling During Zebrafish Cardiac Development

Abstract

The heart is comprised of multiple tissues that contribute to its physiological functions. During development, the growth of myocardium and endocardium is coupled and morphogenetic processes within these separate tissue layers are integrated. Here, we discuss the roles of mechanosensitive Hippo signaling in growth and morphogenesis of the zebrafish heart. Hippo signaling is involved in defining numbers of cardiac progenitor cells derived from the secondary heart field, in restricting the growth of the epicardium, and in guiding trabeculation and outflow tract formation. Recent work also shows that myocardial chamber dimensions serve as a blueprint for Hippo signaling-dependent growth of the endocardium. Evidently, Hippo pathway components act at the crossroads of various signaling pathways involved in embryonic zebrafish heart development. Elucidating how biomechanical Hippo signaling guides heart morphogenesis has direct implications for our understanding of cardiac physiology and pathophysiology.

Ion Channels in the Development and Remodeling of the Aortic Valve

“…Besides this, the hippo/YAP1 signaling pathway known to control the transcription of target genes was also shown to be involved in zebrafish Piezo1-dependent aortic valve development [ 46 ]. Valve formation was delayed by Piezo1 knock-down, and the authors observed thicker leaflets than in WT animals [ 31 ].…”

“…The Piezo1 knock-out embryo exhibits a reduced expression of YAP1 in the two layers which compose the outflow tract, corresponding to the aortic valve, which is composed of endothelial cells and smooth muscle cells. Piezo1 knock-out embryos also exhibit an increase in the mechano-sensitive transcription factor klf2a [ 31 , 46 ]. This factor is known as a flow-responsive gene in zebrafish as well as in vertebrates [ 33 ].…”

“…This factor is known as a flow-responsive gene in zebrafish as well as in vertebrates [ 33 ]. Collectively these data suggest that Piezo1 appears to modulate outflow tract development by inhibiting klf2a in the endothelium and stimulating Yap1 in the endothelium and smooth muscle [ 46 ].…”

Heart in a dish – choosing the rightin vitromodel

“…One of the underlying reasons is the low predictive value of the commonly used models used in preclinical research ( Eder et al, 2016 ). Although animal models such as mouse, chicken and zebrafish have proven essential for studying the basic principles of cardiogenesis ( Brade et al, 2013 ; Buckingham et al, 2005 ; Kirby, 2007 ; Bornhorst and Abdelilah-Seyfried, 2021 ), their capability to recapitulate human-specific aspects of heart development, histogenesis and physiology is limited. Apart from ethical considerations, high cost and time demands associated with animal models, a major drawback is the interspecies variability at the physiological and genetic levels, which limits the translatability of respective findings to the treatment of humans ( Brandão et al, 2017 ; Davis et al, 2011a , b ; Wobus and Löser, 2011 ).…”