Lymphatic Defects in Zebrafish Mutants Are Exacerbated by Perturbed VEGFC Signaling, While Masked by Elevated Expression.

Mutations in the transcription factor-coding gene , the growth factor-coding gene and its receptor-coding gene cause primary lymphedema in humans. In mammals, SOX18, together with COUP-TFII/NR2F2, activates the expression of , a master regulator in lymphatic identity and development. Knockdown studies have also suggested an involvement of Sox18, Coup-tfII/Nr2f2, and Prox1 in zebrafish lymphatic development. Mutants in the corresponding genes initially failed to recapitulate the lymphatic defects observed in morphants. In this paper, we describe a novel zebrafish mutant allele, , which behaves as a null. The formation of the lymphatic thoracic duct is affected in homozygous mutants, but defects are milder in both zygotic and maternal-zygotic mutants than in morphants. Remarkably, in mutants, the expression of the closely related gene is elevated where lymphatic precursors arise. Sox7 could thus mask the absence of a functional Sox18 protein and account for the mild lymphatic phenotype in mutants, as shown in mice. Partial knockdown of exacerbates lymphatic defects in mutants, making them visible in heterozygotes. Our data thus reinforce the genetic interaction between Sox18 and Vegfc in lymphatic development, previously suggested by knockdown studies, and highlight the ability of Sox7 to compensate for Sox18 lymphatic dysfunction.