Svep1 is a binding ligand of Tie1 and affects specific aspects of facial lymphatic development in a Vegfc-independent manner
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eLife assessment
This work reveals that lymphatic vascular development can occur independent of VegfC signaling, and that genetic interactions between a large extracellular matrix protein Svep1 and Tie1 receptor are important for the development of facial lymphatics and other aspects of lymphatic vascular development. The data link Svep1 to Tie1 signaling via elegant genetic experiments and provide important insights into a complex signaling pathway that is widely utilized in vascular development. The genetic evidence is convincing in supporting the findings that Tie1 but not Tie2 interacts with Svep1 in aspects of lymphangiogenesis.
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Abstract
Multiple factors are required to form functional lymphatic vessels. Here, we uncover an essential role for the secreted protein Svep1 and the transmembrane receptor Tie1 during the development of subpopulations of the zebrafish facial lymphatic network. This specific aspect of the facial network forms independently of Vascular endothelial growth factor C (Vegfc) signalling, which otherwise is the most prominent signalling axis in all other lymphatic beds. Additionally, we find that multiple specific and newly uncovered phenotypic hallmarks of svep1 mutants are also present in tie1 , but not in tie2 or vegfc mutants. These phenotypes are observed in the lymphatic vasculature of both head and trunk, as well as in the development of the dorsal longitudinal anastomotic vessel under reduced flow conditions. Therefore, our study demonstrates an important function for Tie1 signalling during lymphangiogenesis as well as blood vessel development in zebrafish. Furthermore, we show genetic interaction between svep1 and tie1 in vivo, during early steps of lymphangiogenesis, and demonstrate that zebrafish as well as human Svep1/SVEP1 protein bind to the respective Tie1/TIE1 receptors in vitro. Since compound heterozygous mutations for SVEP1 and TIE2 have recently been reported in human glaucoma patients, our data have clinical relevance in demonstrating a role for SVEP1 in TIE signalling in an in vivo setting.
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eLife assessment
This work reveals that lymphatic vascular development can occur independent of VegfC signaling, and that genetic interactions between a large extracellular matrix protein Svep1 and Tie1 receptor are important for the development of facial lymphatics and other aspects of lymphatic vascular development. The data link Svep1 to Tie1 signaling via elegant genetic experiments and provide important insights into a complex signaling pathway that is widely utilized in vascular development. The genetic evidence is convincing in supporting the findings that Tie1 but not Tie2 interacts with Svep1 in aspects of lymphangiogenesis.
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Reviewer #1 (Public Review):
This paper by Hubmann et al investigates the role of a large ECM protein in lymphangiogenesis using the zebrafish model to test genetic interactions and with state-of-the-art reporter readouts to evaluate expression patterns and vascular behaviors. The experiments examine the effects of svep1 deletion on facial lymphatics and produce the surprising result that svep1 and vegfc appear to be required in non-overlapping areas of this lymphatic vascular bed. They then use these tools and mutants for tie1 or tie2 to examine genetic interactions in this area and in parachordal lymphangioblast migration in the trunk, showing that tie1 but not tie2 shows epistasis with svep1. The data are overall rigorous and quantified to show the statistical significance of the stated results. The work provides important insights …
Reviewer #1 (Public Review):
This paper by Hubmann et al investigates the role of a large ECM protein in lymphangiogenesis using the zebrafish model to test genetic interactions and with state-of-the-art reporter readouts to evaluate expression patterns and vascular behaviors. The experiments examine the effects of svep1 deletion on facial lymphatics and produce the surprising result that svep1 and vegfc appear to be required in non-overlapping areas of this lymphatic vascular bed. They then use these tools and mutants for tie1 or tie2 to examine genetic interactions in this area and in parachordal lymphangioblast migration in the trunk, showing that tie1 but not tie2 shows epistasis with svep1. The data are overall rigorous and quantified to show the statistical significance of the stated results. The work provides important insights into a complex signaling pathway that is widely utilized in vascular development. The evidence is convincing in supporting the findings and is predicted to be of interest to vascular biologists and others interested in Tie/Tek signaling such as cancer biologists.
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Reviewer #2 (Public Review):
In their current manuscript Hussmann et al., present a very detailed phenotypic analysis of the role of svep1 in lymphatic development in zebrafish. They show that svep1 is essential for the development of particular aspects of facial lymphatics (the FCLV and BLECs) in a fashion complementary to VEGF-C. Furthermore, they show that the loss of tie1 phenocopies svep1 mutants not only with respect to lymphatic defects but also in blood vessels (DLAV).
Overall, the manuscript is clearly written, the experiments are carefully executed, and the quality of data is very high and support the author's main conclusions: 1) that Svep1 and Tie1 genetically interact during lymphatic and blood vessel development and 2) that this function is independent and complementary to VEGF-C. 3) The authors confirm and extend on a …
Reviewer #2 (Public Review):
In their current manuscript Hussmann et al., present a very detailed phenotypic analysis of the role of svep1 in lymphatic development in zebrafish. They show that svep1 is essential for the development of particular aspects of facial lymphatics (the FCLV and BLECs) in a fashion complementary to VEGF-C. Furthermore, they show that the loss of tie1 phenocopies svep1 mutants not only with respect to lymphatic defects but also in blood vessels (DLAV).
Overall, the manuscript is clearly written, the experiments are carefully executed, and the quality of data is very high and support the author's main conclusions: 1) that Svep1 and Tie1 genetically interact during lymphatic and blood vessel development and 2) that this function is independent and complementary to VEGF-C. 3) The authors confirm and extend on a previous study (Jiang et al. 2020) showing that tie2 (tek) has no overt role in vascular development in zebrafish in blood as well as in lymphatic vessels.
The strength of the paper lies in the careful combination and comparison of different mutant alleles and the use of state-of-the-art imaging. These analyses show that Svep1 and Tie1 interact at the genetic level. In vivo cell tracking experiments show that Tie1 and Svep1 regulate particular aspects of lymphatic cell migration.
An obvious remaining question concerns the epistatic relationship and the molecular mechanism of Tie1/Svep1 interaction. The authors suggest a non-autonomous requirement of Svep1 in the ECM regulating the availability of Tie1 ligands (Ang-1/-2?) in LECs. Since bona fide ligands for Tie1 have not yet been identified in zebrafish further studies will be needed to test this model.
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Reviewer #3 (Public Review):
This manuscript describes a Vegfc-independent mechanism of lymphatic vessel formation that is controlled by Svep1 and an orphan endothelial receptor tyrosine kinase Tie1. Based on similarities in the phenotype of svep1 and tie1 mutant zebrafish in the head and trunk vasculature, as well as genetic interaction between the two during parachordal lymphangioblast migration, the authors propose that svep1 is a component of the tie1 signaling pathway. Specifically, svep1 and tie1 mutants show a unique phenotype with the absence of facial collecting lymphatic vessel (that forms in Vegfc mutants) while other facial vessels (that are dependent on Vegfc/Vegfr3 signaling) were only partially affected. Svep1 and tie1 mutants also show similar defects in the formation of brain LECs, the number and migration of …
Reviewer #3 (Public Review):
This manuscript describes a Vegfc-independent mechanism of lymphatic vessel formation that is controlled by Svep1 and an orphan endothelial receptor tyrosine kinase Tie1. Based on similarities in the phenotype of svep1 and tie1 mutant zebrafish in the head and trunk vasculature, as well as genetic interaction between the two during parachordal lymphangioblast migration, the authors propose that svep1 is a component of the tie1 signaling pathway. Specifically, svep1 and tie1 mutants show a unique phenotype with the absence of facial collecting lymphatic vessel (that forms in Vegfc mutants) while other facial vessels (that are dependent on Vegfc/Vegfr3 signaling) were only partially affected. Svep1 and tie1 mutants also show similar defects in the formation of brain LECs, the number and migration of parachordal lymphangioblasts from the horizontal myoseptum, and DLAV formation. In contrast, tie2, which is the major angiopoietin receptor in mammals, was found to be dispensable for vascular development in zebrafish.
The presented experiments are performed well and the data are conclusive. The novel findings are the identification of a role of tie1 in zebrafish lymphatic development, and svep1 as a component of the tie1 signaling pathway. The latter raises the possibility that svep1 regulates the activity of Angiopoietin or even acts as a ligand for tie1. However, the conclusion on Svep1 and Tie1 being in the same pathway is based solely on the comparison of mutant phenotypes and genetic interaction studies. Any biochemical data on how svep1 regulates tie1 signaling would greatly strengthen this conclusion.
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