Abstract
ABSTRACTOrgan morphogenesis is driven by a wealth of tightly orchestrated cellular behaviors, which ensure proper organ assembly and function. Many of these cell activities involve cell-cell interactions and remodeling of the F-actin cytoskeleton. Here, we analyze the requirement for Rasip1 (Ras-interacting protein 1), an endothelial-specific regulator of junctional dynamics, during blood vessel formation. Phenotype analysis of rasip1 mutants in zebrafish embryos reveals distinct functions of Rasip1 during sprouting angiogenesis, anastomosis and lumen formation. During angiogenic sprouting, loss of Rasip1 causes cell pairing defects due to a destabilization of tricellular junctions, indicating that stable tricellular junctions are essential to maintain multicellular organization within the sprout. During anastomosis, Rasip1 is required to establish a stable apical membrane compartment; rasip1 mutants display ectopic, reticulated junctions and the apical compartment is frequently collapsed. Loss of Ccm1 and Heg1 function mimics the junctional defects of rasip1 mutants. Furthermore, downregulation of ccm1 and heg1 leads to a delocalization of Rasip1 at cell junctions, indicating that junctional tethering of Rasip1 is required for its function in junction formation and stabilization during sprouting angiogenesis.
Highlights
The cardiovascular system is the first organ to become functional during embryonic development
Loss of Rasip1 function causes broad vascular defects To investigate the role of Rasip1 in vascular morphogenesis, we employed CRISPR/Cas9 technology to generate several mutant alleles, namely rasip1ubs23, rasip1ubs24 and rasip1ubs28, respectively (Fig. S1)
The rasip1ubs28 allele comprises a deletion of about 35 kb, including the rasip1 coding region from exon 3 to 16, resulting in a severely truncated protein lacking the Ras-association, Forkheadassociation and Dilute domains (Fig. S1A)
Summary
The cardiovascular system is the first organ to become functional during embryonic development. Handling Editor: Steve Wilson Received 6 October 2020; Accepted 8 June 2021 the vasculature tree via sprouting angiogenesis, vascular remodeling and adaptation of blood vessel diameter. Vascular morphogenesis is driven by a wealth of dynamic cellular behaviors, which are regulated by molecular as well as physical cues, and are characterized by an extraordinary plasticity (Adams and Alitalo, 2007; Baeyens et al, 2016; Duran et al, 2017). Blood vessel morphogenesis and remodeling are accomplished by endothelial cell behaviors, including cell migration, cell rearrangement and cell shape changes (Betz et al, 2016). This repertoire of dynamic behaviors allows endothelial cells to respond rapidly to different contextual cues, for example during angiogenic sprouting, anastomosis, pruning, diapedesis or regeneration
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