Abstract
Nonaggregative multicellularity requires strict control of cell number. The Hippo signaling pathway coordinates cell proliferation and apoptosis and is a central regulator of organ size in animals. Recent studies have shown the presence of key members of the Hippo pathway in nonbilaterian animals, but failed to identify this pathway outside Metazoa. Through comparative analyses of recently sequenced holozoan genomes, we show that Hippo pathway components, such as the kinases Hippo and Warts, the coactivator Yorkie, and the transcription factor Scalloped, were already present in the unicellular ancestors of animals. Remarkably, functional analysis of Hippo components of the amoeboid holozoan Capsaspora owczarzaki, performed in Drosophila melanogaster, demonstrate that the growth-regulatory activity of the Hippo pathway is conserved in this unicellular lineage. Our findings show that the Hippo pathway evolved well before the origin of Metazoa and highlight the importance of Hippo signaling as a key developmental mechanism predating the origin of Metazoa.
Highlights
The emergence of multicellularity represents one of the most important transitions in animal evolution
Phylogenetic analysis clusters them unequivocally with metazoan Yki homologs with high nodal support and well differentiated from the WWP1 and other ubiquitin ligases that contain WW domains (Supplemental Figure S1). All these non-metazoan Yki homologs contain highly conserved functional sites like the Hippo pathway responsive phosphorylation site S168/127 and the N-terminal homology region that is critical for interaction with Sd/TEAD transcription factor (Figure 2A)
Using a well-characterized luciferase reporter driven by the minimal Hippo-Responsive Element (HRE) derived from the Hippo target gene diap1 (Wu et al, 2008), we found that co-expression of Capsaspora owczarzaki (Co)-Sd and Capsaspora Yorkie (Co-Yki) stimulated the transcription of the HRE-luciferase reporter in Drosophila S2R+ cells (Figure 4B)
Summary
The Hippo signaling pathway coordinates cell proliferation and apoptosis and is a central regulator of organ size in animals. Recent studies have shown the presence of key members of the Hippo pathway in nonbilaterian animals, but failed to identify this pathway outside Metazoa. Through comparative analyses of recently sequenced holozoan genomes, we show that Hippo pathway components, such as the kinases Hippo and Warts, the co-activator Yorkie and the transcription factor Scalloped, were already present in the unicellular ancestors of animals. Functional analysis of Hippo components of the amoeboid holozoan Capsaspora owczarzaki, performed in Drosophila, demonstrate that the growth-regulatory activity of the Hippo pathway is conserved in this unicellular lineage.
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