Genetic and Functional Dissection of the Hippo Pathway in Caenorhabditis elegans

Abstract

The Hippo (Hpo) pathway is a conserved signaling pathway which has essential roles in early development of organisms. It regulates organ size homeostasis via controlling cell proliferation and apoptosis and mediates polarized cell differentiation. In Caenorhabditis elegans, although several components of the Hpo pathway and genetic interactions among them were reported, the physiological functions of the Hpo pathway are relatively unknown. Here, using many genetic approaches, I elucidated that the conserved Hpo pathway functions in the apicobasal polarity maintenance of growing intestinal membrane and the maintenance of structural integrity of neurons in C. elegans. In polarized epithelial cells, functionally distinct membrane domains are established and tightly maintained during development. Although many conserved polarity determinants have been identified, the mechanism to maintain the apicobasal polarity in expanding membranes is not yet fully understood. From genetic screenings, I delineated the conserved NFM-1-WTS-1-YAP-1 signaling cascade plays a role in the maintenance of apicobasal polarity by regulating a conserved P-type ATPase, tat-2. The Hpo pathway-mediated tat-2 regulation is important to maintain apicobasal membrane identities, which leads to polarized sorting of newly synthesized proteins in the expanding membrane. I also defined neuronal roles of the Hpo pathway in C. elegans. I found that yap-1, the worm homolog of YAP/Yki, acts in asymmetric development of neurons. In addition to its functions in neuronal development, I found that the Hpo pathway is required to maintain structural integrity of neurons. I observed that worms which lack the Hpo pathway and the Wnt pathway showed defects in neurons such that the mutant exhibited disintegrated neurons precociously. Considering that structural and functional decline of neurons is a hallmark of neuronal aging, my works will provide a molecular mechanism for neuronal aging. In summary, I report the developmental functions of the Hpo pathway in C. elegans intestine and neurons, and the post developmental roles of the Hpo pathway in the structural maintenance of neurons.