Vegfc acts through ERK to induce sprouting and differentiation of trunk lymphatic progenitors.
Development
; 143(20): 3785-3795, 2016 10 15.
Article
em En
| MEDLINE
| ID: mdl-27621059
Vascular endothelial growth factor C (Vegfc) activates its receptor, Flt4, to induce lymphatic development. However, the signals that act downstream of Flt4 in this context in vivo remain unclear. To understand Flt4 signaling better, we generated zebrafish bearing a deletion in the Flt4 cytoplasmic domain that eliminates tyrosines Y1226 and 1227. Embryos bearing this deletion failed to initiate sprouting or differentiation of trunk lymphatic vessels and did not form a thoracic duct. Deletion of Y1226/7 prevented ERK phosphorylation in lymphatic progenitors, and ERK inhibition blocked trunk lymphatic sprouting and differentiation. Conversely, endothelial autonomous ERK activation rescued lymphatic sprouting and differentiation in flt4 mutants. Interestingly, embryos bearing the Y1226/7 deletion formed a functional facial lymphatic network enabling them to develop normally to adulthood. By contrast, flt4 null larvae displayed hypoplastic facial lymphatics and severe lymphedema. Thus, facial lymphatic vessels appear to be the first functional lymphatic network in the zebrafish, whereas the thoracic duct is initially dispensable for lymphatic function. Moreover, distinct signaling pathways downstream of Flt4 govern lymphatic morphogenesis and differentiation in different anatomical locations.
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MEDLINE
Assunto principal:
Peixe-Zebra
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Proteínas de Peixe-Zebra
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Vasos Linfáticos
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Fator C de Crescimento do Endotélio Vascular
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MAP Quinases Reguladas por Sinal Extracelular
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article