Abstract
Lymphatic vascular development involves specification of lymphatic endothelial progenitors that subsequently undergo sprouting, proliferation and tissue growth to form a complex second vasculature. The Hippo pathway and effectors Yap and Taz control organ growth and regulate morphogenesis and cellular proliferation. Yap and Taz control angiogenesis but a role in lymphangiogenesis remains to be fully elucidated. Here we show that YAP displays dynamic changes in lymphatic progenitors and Yap1 is essential for lymphatic vascular development in zebrafish. Maternal and Zygotic (MZ) yap1 mutants show normal specification of lymphatic progenitors, abnormal cellular sprouting and reduced numbers of lymphatic progenitors emerging from the cardinal vein during lymphangiogenesis. Furthermore, Yap1 is indispensable for Vegfc-induced proliferation in a transgenic model of Vegfc overexpression. Paracrine Vegfc-signalling ultimately increases nuclear YAP in lymphatic progenitors to control lymphatic development. We thus identify a role for Yap in lymphangiogenesis, acting downstream of Vegfc to promote expansion of this vascular lineage.
Highlights
During embryonic development, the lymphatic vascular network derives from pre-existing veins
In the E9-9.5 mouse embryo, complex, multicellular lymphatic vessels are generated from a limited pool of lymphatic endothelial cell (LEC) progenitors first specified along the cardinal veins (Oliver and Srinivasan, 2010; Wigle and Oliver, 1999)
Expression was detected throughout the dorsal aorta (DA), the intersegmental vessels (ISVs) and posterior cardinal vein (PCV) at 30 hpf, parachordal LEC progenitors (PLs, 2 dpf) and the thoracic duct at 5 dpf (Figure 1A,B, Video 1)
Summary
The lymphatic vascular network derives from pre-existing veins. In the E9-9.5 mouse embryo, complex, multicellular lymphatic vessels are generated from a limited pool of lymphatic endothelial cell (LEC) progenitors first specified along the cardinal veins (Oliver and Srinivasan, 2010; Wigle and Oliver, 1999). LEC progenitors sprout and progressively colonise embryonic tissues over developmental time (Hagerling et al, 2013; Koltowska et al, 2013). A complex lymphatic vasculature is established within just a few days and from a very limited number of progenitors (Koltowska et al, 2015a; Nicenboim et al, 2015; Shin et al, 2016). Beginning from around 32–34 hr post fertilisation (hpf), Grimm et al eLife 2019;8:e42881.
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