20 2 ECM regulates morphogenesis and function of ciliated sensory organs in 21 Caenorhabditis elegans 22 ABSTRACT 23 Cilia and extracellular vesicles (EVs) are signaling organelles that play important 24 roles in human health and disease. In C. elegans and mammals, the Autosomal 25 Dominant Polycystic Kidney Disease (ADPKD) gene products polycystin-1 and 26polycystin-2 localize to both cilia and EVs, act in the same genetic pathway, and 27 function in a sensory capacity, suggesting ancient conservation. Hence, the nematode 28 offers an excellent system in which to address central questions regarding the biology of 29 cilia, EVs, and the polycystins. We discovered an unexpected role of the mec-1, mec-5, 30 and mec-9 genes encoding extracellular matrix (ECM) components. We determined that 31 these ECM encoding genes regulate polycystin localization and function, ciliary EV 32 release, cilia length, dendritic morphology, and neuron-glia interactions. Abnormal ECM 33 and fibrosis are observed in ciliopathies such as ADPKD, nephronophthisis, and Biedl Syndrome. Our studies reveal multifaceted roles for ECM proteins in the ciliated 35 nervous system of the worm and provide a powerful new in vivo model to study the 36 relationship between ECM, the polycystins, and ciliopathies. 37 38 39 40 41 42 Cilia are antenna-like structures that project from many eukaryotic cells (WOOD 43 AND ROSENBAUM 2015). Cilia play essential roles in human development and health, with 44 ciliary defects resulting in syndromic ciliopathies (REITER AND LEROUX 2017). Cilia are 45 endowed with receptors, channels, and signaling components, enabling cilia to act as 46 cellular sensors. In addition to their sensory abilities, cilia may transmit signals via 47 submicroscopic extracellular vesicles (WANG AND BARR 2018; WOOD AND ROSENBAUM 48 2015). The mechanisms that enable a cilium to simultaneously send and receive 49 information remain mysterious.50Cilia and the extracellular matrix (ECM) share an intimate association, with cilia 51 projecting into and being surrounded by ECM (SEEGER-NUKPEZAH AND GOLEMIS 2012). 52ECM is made up of a network of interacting proteins that surround and support cells for 53 adhesive, structural and signaling functions (HYNES 2009). ECM is necessary for tissue 54 morphogenesis and homeostasis throughout the lifespan of an organism and 55 dynamically interacts with and regulates body systems, organs, and tissues. In the 56 brain and nervous system, ECM is important for neuronal development, anatomy, and 57 synaptic transmission. Dysregulation of ECM contributes to pathological conditions 58 such as invasive cancer and fibrosis (BONNANS et al. 2014). Fibrosis and abnormal ECM 59 are observed in ciliopathies such as autosomal dominant polycystic kidney disease 60 (ADPKD), nephronophthisis, and Bardet-Biedl Syndrome (SONG et al. 2017). 61 ADPKD is a genetic disorder characterized by the presence of fluid filled cysts 62 which form on and in the kidney epithelia lining renal tubules that replace normally 63 funct...
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