The recent advances and future perspectives of genetic compensation studies in the zebrafish model.

Genetic compensation is a remarkable biological concept to explain the genetic robustness in an organism to maintain its fitness and viability if there is a disruption occurred in the genetic variation by mutation. However, the underlying mechanism in genetic compensation remain unsolvable. The initial concept of genetic compensation has been studied in model organisms when there was a discrepancy between knockout-mediated and knockdown-mediated phenotypes. In the zebrafish model, several studies have reported that zebrafish mutants did not exhibit severe phenotype as shown in zebrafish morphants for the same genes. This phenomenon in zebrafish mutants but not morphants is due to the response of genetic compensation. In 2019, two amazing works partially uncovered genetic compensation could be triggered by the upregulation of compensating genes through regulating NMD and/or PTC-bearing mRNA in collaboration with epigenetic machinery in mutant zebrafish. In this review, we would like to update the recent advances and future perspectives of genetic compensation studies, which including the hypothesis of time-dependent involvement and addressing the discrepancy between knockout-mediated and knockdown-mediated to study gene function in the zebrafish model. At last, the study of genetic compensation could be a potential therapeutic strategy to treat human genetic disorder related diseases.

Noncanonical protease-activated receptor 1 regulates lymphatic differentiation in zebrafish.

The differentiation of lymphatic progenitors is a crucial step in lymphangiogenesis. However, its underlying mechanism remains unclear. Here, we found that noncanonical protease-activated receptor 1 (par1) regulates the differentiation of lymphatic progenitors in zebrafish embryos. Loss of par1 function impaired lymphatic differentiation by downregulating prox1a expression in parachordal lymphangioblasts and caused compromised thoracic duct formation in zebrafish. Meanwhile, the G protein gnai2a, a par1 downstream effector, was selectively required for lymphatic development in zebrafish, and its mutation mimicked the lymphatic phenotype observed in par1 mutants. Interestingly, mmp13, but not thrombin, was required for lymphatic development in zebrafish. Furthermore, analyses of genetic interactions confirmed that mmp13b serves as a par1 upstream protease to regulate lymphatic development in zebrafish embryos. Mechanistically, par1 promotes flt4 expression and phospho-Erk1/2 activity in the posterior cardinal vein. Taken together, our findings highlight a function of par1 in the regulation of lymphatic differentiation in zebrafish embryos.

The blood flow-klf6a-tagln2 axis drives vessel pruning in zebrafish by regulating endothelial cell rearrangement and actin cytoskeleton dynamics.

Recent studies have focused on capillary pruning in various organs and species. However, the way in which large-diameter vessels are pruned remains unclear. Here we show that pruning of the zebrafish caudal vein (CV) from ventral capillaries of the CV plexus in different transgenic embryos is driven by endothelial cell (EC) rearrangement, which involves EC nucleus migration, junction remodeling, and actin cytoskeleton remodeling. Further observation reveals a growing difference in blood flow velocity between the two vessels in CV pruning in zebrafish embryos. With this model, we identify the critical role of Kruppel-like factor 6a (klf6a) in CV pruning. Disruption of klf6a functioning impairs CV pruning in zebrafish. klf6a is required for EC nucleus migration, junction remodeling, and actin cytoskeleton dynamics in zebrafish embryos. Moreover, actin-related protein transgelin 2 (tagln2) is a direct downstream target of klf6a in CV pruning in zebrafish embryos. Together these results demonstrate that the klf6a-tagln2 axis regulates CV pruning by promoting EC rearrangement.

Progress and prospects of mechanotransducers in shear stress-sensitive signaling pathways in association with arteriovenous malformation.

Arteriovenous malformations are congenital vascular lesions characterized by a direct and tangled connection between arteries and veins, which disrupts oxygen circulation and normal blood flow. Arteriovenous malformations often occur in the patient with hereditary hemorrhagic telangiectasia. The attempts to elucidate the causative factors and pathogenic mechanisms of arteriovenous malformations are now still in progress. Some studies reported that shear stress in blood flow is one of the factors involved in arteriovenous malformations manifestation. Through several mechanotransducers harboring the endothelial cells membrane, the signal from shear stress is transduced towards the responsible signaling pathways in endothelial cells to maintain cell homeostasis. Any disruption in this well-established communication will give rise to abnormal endothelial cells differentiation and specification, which will later promote arteriovenous malformations. In this review, we discuss the update of several mechanotransducers that have essential roles in shear stress-induced signaling pathways, such as activin receptor-like kinase 1, Endoglin, Notch, vascular endothelial growth factor receptor 2, Caveolin-1, Connexin37, and Connexin40. Any disruption of these signaling potentially causes arteriovenous malformations. We also present some recent insights into the fundamental analysis, which attempts to determine potential and alternative solutions to battle arteriovenous malformations, especially in a less invasive and risky way, such as gene treatments.