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Mechanotransduction in Cardiovascular Development and Regeneration: A Genetic Zebrafish Model
Published in Juhyun Lee, Sharon Gerecht, Hanjoong Jo, Tzung Hsiai, Modern Mechanobiology, 2021
Rongsong Li, Kyung In Baek, Chih-Chiang Chang, Bill Zhou, Tzung Hsiai
To elucidate the role and mechanism of hemodynamic forces on trabeculation via notch signaling, Lee et al. took advantage of genetic manipulation in zebrafish and lowered hemodynamic shear forces via (i) microinjection of gata1a MO at one- to four-cell stage to reduce hematopoiesis and viscosity by 90% [90, 91], (ii) microinjection of troponin T type 2a (tnnt2a) MO to arrest cardiomyocyte contraction in embryos [92, 93], and (3) genetic mutation of the weak atriumm58 mutant to inhibit atrial contraction [82, 94]. Lowered hemodynamic forces are companied with the inhibition of Notch signaling and trabeculation. Utilizing the Tg(flk-1:mCherry, tp1:gfp) fish line, shear stress-activated Notch signaling is confirmed to be localized to the endocardium. Endocardial activation of notch signaling is required for trabeculation. The zebrafish clo mutant, in which the endothelial line was abolished, developed a small and thin ventricle [95–97] along with reduced expression of cardiac Notch ligands, receptor, and target genes compared with that of the wild type [89]. Notch activation in the endocardium results in the transcription of EephrinB2, which in turn upregulates Nrg1 [98]. As a secreted factor, Nrg1 signals to the adjacent cardiomyocytes to promote trabeculation. Disruption of Nrg1 expression after ischemic insult impairs cardiac contractility [99], whereas Nrg1 preconditioning confers cardiac protection from ischemic injury [100]. In parallel, Notch activity in the endocardium activates BMP10 expression in the adjacent myocytes to promote proliferation [98]. Unlike mouse development, Nrg1/ErbB2 signaling contributes to both proliferation and differentiation of cardiomyocytes for trabeculation in zebrafish [101]. The advantages of the zebrafish model have enabled researchers to establish the essential role of mechanosensitive Notch signaling in promoting cardiac trabeculation involving ephrinB2, Nrg1, and ErbB2[98, 101, 102] (Fig. 6.3).
Agrochemical-mediated cardiotoxicity in zebrafish embryos/larvae: What we do and where we go
Published in Critical Reviews in Environmental Science and Technology, 2023
Yang Yang, Yue Tao, Zixu Li, Yunhe Cui, Jinzhu Zhang, Ying Zhang
In studies using zebrafish as a model, the Notch signaling pathway was shown to play an essential role in cardiac looping and trabeculation. Although cardiomyocyte migration (cardiac tube rotation), mechanosensing (bending forces) and the myocardial cytoskeleton (rotational forces) are involved in cardiac looping (Baker et al., 2008; Galli et al., 2008; Linask and Vanauker, 2007), the complex molecular mechanisms involved remain unclear. Nevertheless, abnormal circulation in the loft zebrafish mutant is rescued by over-expression of the Notch intracellular domain, emphasizing the importance of the Notch signaling pathway in establishing cardiac circulation (Zhou et al., 2021). Furthermore, numerous studies of zebrafish models showed that correct expression of the Notch signaling pathway among different cells is essential for trabeculation. The shear and mechanical stresses exerted on the ventricular wall by blood flow and cardiac contraction activate Notch signaling between endocardial cells and their neighboring cells and promote the secretion of neuregulin (Nrg1) from the latter cells (Samsa et al., 2015). The receptor protein Erbb2 on cardiac myocytes activates its own differentiation and proliferation upon recognizing Nrg1 to drive trabeculation. Cardiomyocytes that recognize Nrg1 also activate the expression of Notch signaling in neighboring cardiomyocytes, thereby inhibiting the expression of erbb2 in neighboring cardiomyocytes to prevent them from becoming trabeculae (Han et al., 2016).