Abstract
Tie1 is a receptor tyrosine kinase expressed in endothelial cells, where it modulates Angiopoietin/Tie2 signaling. Previous studies have shown that mouse Tie1 mutants exhibit severe cardiovascular defects; however, much remains to be learned about the role of Tie1, especially during cardiac development. To further understand Tie1 function, we generated a zebrafish tie1 mutant line. Homozygous mutant embryos display reduced endothelial and endocardial cell numbers and reduced heart size. Live imaging and ultrastructural analyses at embryonic stages revealed increased cardiac jelly thickness as well as cardiomyocyte defects, including a loss of sarcomere organization and altered cell shape. Transcriptomic profiling of embryonic hearts uncovered the downregulation of tll1, which encodes a Tolloid-like protease, in tie1−/− compared with wild-type siblings. Using mRNA injections into one-cell stage embryos, we found that tll1 overexpression could partially rescue the tie1 mutant cardiac phenotypes including the endocardial and myocardial cell numbers as well as the cardiac jelly thickness. Altogether, our results indicate the importance of a Tie1-Tolloid-like 1 axis in paracrine signaling during cardiac development.
Highlights
The vertebrate heart first appears as a linear tube which through several morphological changes, including jogging, looping, trabeculation and valvulogenesis, develops into a fully functional organ (Yelon, 2001; Bakkers, 2011; Staudt and Stainier, 2012)
Using mRNA injections into one-cell stage embryos, we found that tll1 overexpression could partially rescue the tie1 mutant cardiac phenotypes including the endocardial and myocardial cell numbers as well as the cardiac jelly thickness
Numerous studies have reported the importance of the Angiopoietin/ Tie2 signaling pathway in cardiovascular development
Summary
The vertebrate heart first appears as a linear tube which through several morphological changes, including jogging, looping, trabeculation and valvulogenesis, develops into a fully functional organ (Yelon, 2001; Bakkers, 2011; Staudt and Stainier, 2012). Bmp and bmp2b expressed in cardiomyocytes regulate endocardial cell number and differentiation in zebrafish (Dietrich et al, 2014; Palencia-Desai et al, 2015). Neuregulin, expressed in endocardial cells, activates the ErbB2 and 4 receptors, expressed in cardiomyocytes, to drive trabeculation (Lee et al, 1995; Meyer et al, 1995; Liu et al, 2010; Peshkovsky et al, 2011; Rasouli and Stainier, 2017). Npas4l (cloche) mutants, which completely lack the endocardium (Stainier et al, 1995; Reischauer et al, 2016), and tal mutants, which lack endocardial cells only in the atrium (Bussmann et al, 2007), exhibit an enlarged atrium and a collapsed ventricle, indicating a role for endocardial cells in cardiomyocyte development. How the endocardium modulates cardiomyocyte differentiation and maturation has yet to be fully explained
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
