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1.
Development ; 149(23)2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-36314606

RESUMEN

The assembly of a mature vascular network involves coordinated endothelial cell (EC) shape changes, including the process of EC elongation. How EC elongation is dynamically regulated in vivo is not fully understood. Here, we have generated a zebrafish mutant that is deficient for the integrin adaptor protein Talin 1 (Tln1). Using a new focal adhesion (FA) marker line expressing endothelial Vinculinb-eGFP, we demonstrate that EC FAs function dynamically and are lost in our tln1 mutants, allowing us to uncouple the primary roles of FAs in EC morphogenesis from the secondary effects that occur due to systemic vessel failure or loss of blood flow. Tln1 loss led to compromised F-actin rearrangements, perturbed EC elongation and disrupted cell-cell junction linearisation in vessel remodelling. Finally, chemical induction of actin polymerisation restored actin dynamics and EC elongation during vascular morphogenesis. Together, we identify that FAs are essential for EC elongation and junction linearisation in flow-pressured vessels and that they influence actin polymerisation in cellular morphogenesis. These observations can explain the severely compromised vessel beds and vascular leakage observed in mutant models that lack integrin signalling. This article has an associated 'The people behind the papers' interview.


Asunto(s)
Adhesiones Focales , Talina , Animales , Adhesiones Focales/metabolismo , Talina/genética , Talina/metabolismo , Actinas/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismo , Células Endoteliales/metabolismo , Integrinas/genética , Integrinas/metabolismo , Adhesión Celular
2.
Dev Dyn ; 251(2): 336-349, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34174014

RESUMEN

BACKGROUND: Lymphatic vascular development is regulated by well-characterized signaling and transcriptional pathways. These pathways regulate lymphatic endothelial cell (LEC) migration, motility, polarity, and morphogenesis. Canonical and non-canonical WNT signaling pathways are known to control LEC polarity and development of lymphatic vessels and valves. PKD1, encoding Polycystin-1, is the most commonly mutated gene in polycystic kidney disease but has also been shown to be essential in lymphatic vascular morphogenesis. The mechanism by which Pkd1 acts during lymphangiogenesis remains unclear. RESULTS: Here we find that loss of non-canonical WNT signaling components Wnt5a and Ryk phenocopy lymphatic defects seen in Pkd1 knockout mice. To investigate genetic interaction, we generated Pkd1;Wnt5a double knockout mice. Loss of Wnt5a suppressed phenotypes seen in the lymphatic vasculature of Pkd1-/- mice and Pkd1 deletion suppressed phenotypes observed in Wnt5a-/- mice. Thus, we report mutually suppressive roles for Pkd1 and Wnt5a, with developing lymphatic networks restored to a more wild type state in double mutant mice. This genetic interaction between Pkd1 and the non-canonical WNT signaling pathway ultimately controls LEC polarity and the morphogenesis of developing vessel networks. CONCLUSION: Our work suggests that Pkd1 acts at least in part by regulating non-canonical WNT signaling during the formation of lymphatic vascular networks.


Asunto(s)
Vasos Linfáticos , Enfermedades Renales Poliquísticas , Animales , Vasos Linfáticos/metabolismo , Ratones , Ratones Noqueados , Morfogénesis/genética , Enfermedades Renales Poliquísticas/genética , Enfermedades Renales Poliquísticas/metabolismo , Proteína Quinasa C , Proteínas Tirosina Quinasas Receptoras/metabolismo , Vía de Señalización Wnt/genética , Proteína Wnt-5a/genética , Proteína Wnt-5a/metabolismo
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