Extracellular matrix regulates morphogenesis and function of ciliated sensory organs

Extracellular matrix (ECM) is made up of a network of interacting proteins that surround and support cells for mechanosensation, attachment, and signaling. Alterations in ECM quality and quantity contribute to many human diseases and disorders (Bruckner-Tuderman & Bruckner, 1998; Kain, 2010). ECM proteins have been implicated in cilia formation, cilia retraction/elongation, and cell-to-cell junction signaling, which are impaired in human ciliopathies (Marta Andrés, Enrique Turiégano, Martin C Göpfert, Inmaculada Canal, & Laura Torroja, 2014a; Rondanino et al., 2011; Seeger-Nukpezah & Golemis, 2012). Abnormal ECM is observed in ciliopathies such as Bardet-Biedl Syndrome, nephronophthisis, and polycystic kidney disease (PKD). PKD1 and PKD2 encode transient receptor potential polycystin channel receptor proteins found in primary cilia of mammalian cells and sensory cilia of Caenorhabditis elegans (C. elegans) neurons. In humans, PKD1 and PKD2 mutations result in autosomal dominant polycystic kidney disease (ADPKD). Given the ancient and evolutionarily conserved role for polycystins in cilia, we used C. elegans to identify new genes required for ciliary receptor localization and found that ECM components play multifaceted roles in ciliated sensory neurons. ECM formation, secretion, and integrity have been shown to be a primary factor in PKD (Mangos et al., 2010). mec-1, mec-5, and mec-9 encode ECM components that play a role in mechanosensation and degenerin/epithelial sodium channel localization in non-ciliated touch receptor neurons (Du, Gu, William, & Chalfie, 1996; Emtage, Gu, Hartwieg, & Chalfie, 2004) . Here, I show the ECM-encoding genes mec-1, mec-5, and mec-9 play complex roles in C. elegans ciliated sensory organs. mec-1 and mec-9 encode proteins that contain multiple epidermal growth factor and Kunitz protease inhibitor domains; mec-5 encodes a collagen (Du et al., 1996; Emtage et al., 2004). These ECM components regulate polycystin localization and polycystin-mediated male mating behaviors; control ciliary, dendritic, and glia integrity; and modulate the release of ciliary extracellular vesicles. Intriguingly, mec-9 has cell-specific functions that are controlled by a short isoform that is differentially expressed in the ciliated nervous system. My findings reveal expanded roles of these ECM components by exposing their activity in ciliated neurons of the worm. I show that ECM proteins regulate aspects of extracellular vesicle biology, control ciliated neuron morphology and activity, and are necessary for ciliary localization of sensory receptors like PKD-2 and LOV-1. These findings expand the options for treatment of ADPKD and advance the front-line research of extracellular vesicle biology.Ph.D.Includes bibliographical referencesby Deanna Michele De Vor