The role of apical-basal polarity regulators in larval epithelia of Caenorhabditis elegans

Abstract

Cell polarity is a fundamental property of cells characterized by the asymmetric distribution of macromolecules such as proteins, lipids, or nucleic acids within the cells, and the enrichment of organelles or cytoskeletal elements at specific cellular sites. In animals, one of the most prevalent polarized cell types is the epithelial cells. The polarization of epithelial cells into apical and basolateral domains is essential for the functioning of epithelia as selectively permeable barriers (Rodriguez-Boulan and Macara, 2014a). Additionally, migrating cells acquire a front to rear axis of polarity that facilitates the formation of protrusive and retractive ends on opposing sides that together guide the movement of the cell (Rappel and Edelstein-Keshet, 2017). Finally, neurons polarize during the process of axon outgrowth (Yogev and Shen, 2017) (Fig. 1). The formation of distinct cellular domains relies on cortically localized polarity determinants. The main and best studied polarity regulators are the members of the Par complex and Crumbs complex that localize apically in epithelial cells and the members of the basolateral module Scribble, which is distributed to the lateral and basal cellular domain. These polarity regulators maintain their cellular territories by complex mechanisms of mutual exclusion. Given its unique role in regulating cell shape and important cellular processes, it is not surprising that disruption of cell polarity causes tissue malformation in different animal systems. Moreover, loss of cell polarity causes disease and is involved in tumorigenesis, metastasis and progression of cancer. Additionally, several polarity regulators are targets of pathogens and oncogenes (Campanale et al., 2017). In this study we investigated the role of cell polarity regulators in larval epithelia of C. elegans. In Chapter 3 we focused on the apical polarity regulators PAR-6, PAR-3, and PKC-3. We performed in vivo protein degradation in the intestine and epidermis and uncovered novel roles for these polarity regulators in epithelial tissue homeostasis.We show that loss of PAR-6 results in growth and molting defects and disrupts the pattern of seam cell divisions. We uncover that PAR-6 plays a role in organizing the non-centrosomal microtubule network through localizing the microtubule organizer NOCA-1/Ninein. In Chapter 4 we show that similarly to PAR-6, LET-413 is also essential for animal growth. LET-413 affects a different aspect of the seam cell epithelium than the apical regulators. The loss of LET-413 disrupts protrusion formation in the seam cells and in turn the reattachment of the seam cells after the asymmetric cell divisions, without affecting the seam cell divisions. Finally, in Chapter 5, we investigated the paradoxical role of the basal polarity regulator LGL-1 in C. elegans. We found that the CDC-42 RhoGAP PAC-1 acts redundantly with LGL-1 in the regulation of epidermal morphogenesis in the late embryogenesis in C. elegans. The research described in this thesis is aimed at dissecting the critical functions of the polarity regulators PAR-6, LET-413, and LGL-1 in important cellular processes. Overall, it contributes to our understanding of the role of the polarization machinery and its downstream pathways in the larval epithelia of C. elegans.