The Evolutionary History of YAP and the Hippo/YAP Pathway

Abstract

The Hippo/YAP pathway plays an important role in animal organ size control, which it exerts by regulating tissue proliferation and apoptosis rates as a response to developmental cues, cell contact, and density. With the ever increasing advance in genome sequencing and analysis tools, our understanding of the animal world and its evolution has greatly increased in the recent years. We used bioinformatic tools to study the evolution of the Hippo/YAP pathway focusing on the transcriptional coactivator YAP, which is a pivotal effector of the pathway. The aim was to establish the origin and mode of development of YAP and its pathway in the animal world. Some pathway members can be already identified in single-celled eukaryotes like the yeast that have preceded multicellular animals. Interestingly, we can find most of the components that are present in human in the sea-anemone Nematostella, which belongs to a very basal group of metazoans, the cnidarians. All the major domains of YAP have been conserved between cnidarians and mammals, and YAP can be identified even in the more basal placozoan clade. We show a very high degree of conservation in regions such as the WW and the TEAD-binding domains, TEAD being the major DNA-binding partner of YAP. Remarkably, we found that the location of an intron in the WW1 genomic region has been invariant along an evolutionary span of over 700 My. We have followed the evolutionary changes in YAP and in other main components of the pathway from the first metazoans such as sponges, described the phylogenetic relationships between the YAP genes and indicated where YAP and other components have been secondarily lost. Evidence is provided that YAP and its binding partner TEAD demonstrate strong coevolution. This gives further support for the importance of the TEAD-YAP association. Beyond contributing to an understanding of the evolutionary history of this pathway, we have provided insights into the "birth" of this pathway, its functions and its mode of operation in animals with different body plans, development, and life styles.

A one-dimensional model of PCP signaling: Polarized cell behavior in the notochord of the ascidian Ciona

“…Complicating the analysis of the PCP pathway in other species are shifting axes, seen for example in the growing Drosophila wing, and overlapping genetic components that function both in PCP signaling and in the growth-promoting Hippo pathway. While genes acting in the Hippo pathway appear to be present in the Ciona genome (Hilman and Gat, 2011), the Ciona notochord neither increases appreciably in volume (Veeman and Smith, 2013), nor undergoes mitoses at these stages, suggesting that much of the confusion regarding polarity versus the simultaneous signaling for cellular growth (Matakatsu and Blair, 2012) may not be present.…”

The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease

“…Activated Dbf2 promotes the phosphorylation and activation of the Cdc14 phosphatase, which dephosphorylates and inhibits Cdk1, ensuring exit from mitosis and accurate cytokinesis. Despite their importance in higher eukaryotes, homologs of TAZ/YAP or TEAD transcription factors remain elusive in yeast (Hilman and Gat, 2011).…”

The Caenorhabditis elegans NF2/Merlin Molecule NFM-1 Nonautonomously Regulates Neuroblast Migration and Interacts Genetically with the Guidance Cue SLT-1/Slit

“…Interestingly, this is a nonautonomous role of NF2 in midline axon guidance, similar to our observation of nfm-1 in C. elegans neuronal migration. The Hippo pathway in C. elegans is poorly conserved (Hilman and Gat 2011), although C. elegans YAP-1 is similar to Yap (Iwasa et al 2013). A role of yap-1 in AQR and PQR migration was not determined.…”