The Hippo Pathway Is Essential for Maintenance of Apicobasal Polarity in the Growing Intestine of Caenorhabditis elegans

Abstract

Although multiple determinants for establishing polarity in membranes of epithelial cells have been identified, the mechanism for maintaining apicobasal polarity is not fully understood. Here, we show that the conserved Hippo kinase pathway plays a role in the maintenance of apicobasal polarity in the developing intestine of Caenorhabditis elegans. We screened suppressors of the mutation in wts-1-the gene that encodes the LATS kinase homolog, deficiency of which leads to disturbance of the apicobasal polarity of the intestinal cells and to eventual death of the organism. We identified several alleles of yap-1 and egl-44 that suppress the effects of this mutation. yap-1 encodes a homolog of YAP/Yki, and egl-44 encodes a homolog of TEAD/Sd. WTS-1 bound directly to YAP-1 and inhibited its nuclear accumulation in intestinal cells. We also found that NFM-1, which is a homolog of NF2/Merlin, functioned in the same genetic pathway as WTS-1 to regulate YAP-1 to maintain cellular polarity. Transcriptome analysis identified several target candidates of the YAP-1-EGL-44 complex including TAT-2, which encodes a putative P-type ATPase. In summary, we have delineated the conserved Hippo pathway in C. elegans consisting of NFM-1-WTS-1-YAP-1-EGL-44 and proved that the proper regulation of YAP-1 by upstream NFM-1 and WTS-1 is essential for maintenance of apicobasal membrane identities of the growing intestine.

Dysfunctional Mechanotransduction through the YAP/TAZ/Hippo Pathway as a Feature of Chronic Disease

“…There seems to be a reciprocal interplay between polarity and Hippo signalling since a recent genetic screen looking for proteins in C. elegans that are involved in maintenance of cell polarity in the growing intestine implicated several components of the Hippo pathway including YAP and TEAD [55].…”

“…The Par complex seems to be important for at the 32-cell stage of embryonic development, whereas at the 16cell stage Par-independent mechanisms are also involved [54]. There seems to be a reciprocal interplay between polarity and Hippo signalling since a recent genetic screen looking for proteins in C. elegans that are involved in maintenance of cell polarity in the growing intestine implicated several components of the Hippo pathway including YAP and TEAD [55].…”

Mutual antagonism between Hippo signaling and cyclin E drives intracellular pattern formation

“…Moreover, both ciliates and animals use Hippo signaling and cyclin E for cell polarization. While in animals Hippo signaling is primarily seen as acting downstream of the Par networks (reviewed in Ajduk and Zernicka-Goetz, 2016 and Richardson and Portela, 2017 ), Hippo signaling also contributes to the proper formation and maintenance of apicobasal polarization ( Genevet et al, 2009 ; Hamaratoglu et al, 2009 ; Lee et al, 2019 ; Nantie et al, 2018 ). In addition to its canonical role in cell cycle progression, cyclin E is required for the establishment of cell polarity in Caenorhabditis elegans embryos ( Cowan and Hyman, 2006 ) and Drosophila melanogaster neuroblasts ( Berger et al, 2005 , 2010 ; Bhat and Apsel, 2004 ).…”

Reciprocal interactions between transforming growth factor beta signaling and collagens: Insights from Caenorhabditis elegans

“…In C. elegans , TOR, BMP, and insulin signaling regulate body size, 35,41,89,90 and cuticle collagens modify body shape and morphology as discussed above. The C. elegans genome does not contain a Hippo homolog, but the downstream components of the Hippo pathway are present including Warts kinase (WTS‐1), and TEAD and YAP/TAZ transcription factors (EGL‐44 and YAP‐1) 91,92 . WTS‐1 has been demonstrated to regulate body size 93 .…”