Lymphangiogenesis, the formation of lymphatic vessels, is tightly linked to the development of the venous vasculature, both at the cellular and molecular levels. Here, we identify a novel role for Sorbs1, the founding member of the SoHo family of cytoskeleton adaptor proteins, in vascular and lymphatic development in the zebrafish. We show that Sorbs1 is required for secondary sprouting and emergence of several vascular structures specifically derived from the axial vein. Most notably, formation of the precursor parachordal lymphatic structures is affected in sorbs1 mutant embryos, severely impacting the establishment of the trunk lymphatic vessel network. Interestingly, we show that Sorbs1 interacts with the BMP pathway and could function outside of Vegfc signaling. Mechanistically, Sorbs1 controls FAK/Src signaling and subsequently impacts on the cytoskeleton processes regulated by Rac1 and RhoA GTPases. Inactivation of Sorbs1 altered cell-extracellular matrix (ECM) contacts rearrangement and cytoskeleton dynamics, leading to specific defects in endothelial cell migratory and adhesive properties. Overall, using in vitro and in vivo assays, we identify Sorbs1 as an important regulator of venous and lymphatic angiogenesis independently of the Vegfc signaling axis. These results provide a better understanding of the complexity found within context-specific vascular and lymphatic development.

中文翻译：

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细胞骨架衔接蛋白 Sorbs1 控制斑马鱼淋巴管和静脉血管的发育

淋巴管生成（淋巴管的形成）在细胞和分子水平上与静脉脉管系统的发育密切相关。在这里，我们确定了 Sorbs1（细胞骨架衔接蛋白 SoHo 家族的创始成员）在斑马鱼血管和淋巴管发育中的新作用。我们表明，Sorbs1 是一些专门源自轴静脉的血管结构的二次发芽和出现所必需的。最值得注意的是，在 sorbs1 突变胚胎中，前体弦旁淋巴结构的形成受到影响，严重影响了躯干淋巴管网络的建立。有趣的是，我们发现 Sorbs1 与 BMP 通路相互作用，并且可以在 Vegfc 信号传导之外发挥作用。从机制上讲，Sorbs1 控制 FAK/Src 信号传导，并随后影响 Rac1 和 RhoA GTPases 调节的细胞骨架过程。Sorbs1 的失活改变了细胞-细胞外基质 (ECM) 接触重排和细胞骨架动力学，导致内皮细胞迁移和粘附特性的特定缺陷。总体而言，通过体外和体内测定，我们确定 Sorbs1 是独立于 Vegfc 信号轴的静脉和淋巴血管生成的重要调节因子。这些结果可以更好地理解特定血管和淋巴管发育中的复杂性。