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The Caenorhabditis Elegans Excretory System: a Model for Tubulogenesis, Cell Fate Specification, and Plasticity

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The Caenorhabditis Elegans Excretory System: a Model for Tubulogenesis, Cell Fate Specification, and Plasticity | WORMBOOK CELL AND ORGANELLE BIOLOGY The Caenorhabditis elegans Excretory System: A Model for Tubulogenesis, Cell Fate Specification, and Plasticity Meera V. Sundaram*,1 and Matthew Buechner† *Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and †Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045 ABSTRACT The excretory system of the nematode Caenorhabditis elegans is a superb model of tubular organogenesis involving a minimum of cells. The system consists of just three unicellular tubes (canal, duct, and pore), a secretory gland, and two associated neurons. Just as in more complex organs, cells of the excretory system must first adopt specific identities and then coordinate diverse processes to form tubes of appropriate topology, shape, connectivity, and physiological function. The unicellular topology of excretory tubes, their varied and sometimes complex shapes, and the dynamic reprogramming of cell identity and remodeling of tube connec- tivity that occur during larval development are particularly fascinating features of this organ. The physiological roles of the excretory system in osmoregulation and other aspects of the animal’s life cycle are only beginning to be explored. The cellular mechanisms and molecular pathways used to build and shape excretory tubes appear similar to those used in both unicellular and multicellular tubes in more complex organs, such as the vertebrate vascular system and kidney, making this simple organ system a useful model for understanding disease processes. KEYWORDS Caenorhabditis elegans; tubulogenesis; excretory–secretory system; WormBook TABLE OF CONTENTS Abstract 35 Introduction to the Excretory System and Unicellular Tubes 37 Unicellular tubes 37 Wrapping: 37 Wrapping and autofusion: 37 Hollowing: 37 Overview of excretory system development 38 Epithelial organization in excretory tube cells 39 Excretory system functions and phenotypes 39 The Excretory Canal Cell 40 Canal cell structure and ultrastructure 40 Lineal origin and Notch dependency of the canal cell 41 Continued Copyright © 2016 by the Genetics Society of America 10.1534/genetics.116.189357 Manuscript received December 1, 2015; accepted for publication March 7, 2016. 1Corresponding author: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, 446a Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA 19104. E-mail: [email protected] Genetics, Vol. 203, 35–63 May 2016 35 CONTENTS, continued Transcription factors important for canal cell differentiation 41 Neural guidance cues and basement membrane steer canal outgrowth 42 Cytoskeletal organization in the growing canals 43 The canal cell likely forms a seamless tube through a hollowing mechanism 44 Models for canal elongation and maintenance 44 Gene products required for most or all lumen growth 44 Cytoskeletal factors and the terminal web 45 Regulators of recycling endosome trafficking 46 Other potential trafficking regulators 47 Canalicular factors 47 Ion transport and fluid flow 48 Future questions 48 The Excretory Duct and Pore Cells 49 Duct and pore tube structure and ultrastructure 49 EGF-Ras-ERK signaling specifies the duct vs. G1 pore fate 49 Transcription factors important for duct or G1 pore differentiation 49 The duct and G1 pore form tubes through a wrapping mechanism 51 AFF-1-dependent duct autofusion converts an autocellular tube to a seamless tube 51 Luminal matrix maintains lumen shape and tube integrity during morphogenesis 51 Future questions 52 The G1-to-G2 Pore Swap 52 Lineal origins and Notch-dependent fate specification of G2 and W 52 Dynamic behavior of G2 and W parallels that of G1 52 Cellular events of the G1-to-G2 pore swap 52 G1 and G2 behave independently 52 A cell-nonautonomous role for LET-60/Ras signaling in G1 pore delamination 53 Why swap? 53 The Excretory Gland 53 Excretory gland structure and ultrastructure 53 Lineal origin and development of the excretory gland 53 Possible functions of the excretory gland 54 The Canal-Associated Neurons 54 CAN structure 54 Transcription factors important for CAN differentiation 54 Regulators of CAN migration and axon outgrowth 54 Possible functions of the CAN neurons 55 Functions of the Nematode Excretory System 55 Adenophorean vs. Secernentean systems 55 Secretory function of the ES system 55 Osmoregulatory function of the excretory system 55 The C. elegans Excretory System as a Model for Understanding Human Diseases 56 36 M. V. Sundaram and M. Buechner Introduction to the Excretory System and Unicellular (Geitmann 2010), and the contractile vacuoles of single-cell Tubes protozoa (Plattner 2015). Understanding how unicellular tubes are formed and maintained has significant health rele- rgans are made up of networks of tubes that transport vance, given the prevalence of such tubes in the microvascu- fluids or gases and mediate exchange of nutrients and O lature and nervous system and their involvement in waste products with surrounding tissues. Each tube type in the cardiovascular disease, stroke, and neuropathies (Feihl network has a distinctive size and shape that facilitates its et al. 2008; Govani and Shovlin 2009; Vallat et al. 2013; particular function. Many biological tubes are constructed Draheim et al. 2014; Haffner et al. 2016). Several different from polarized epithelial cells, with the apical surface forming mechanisms for forming unicellular tubes have been pro- the lumen, while the basal surface forms the outside of the posed, although none are very well understood at the tube facing other tissues or body cavity (Figure 1). Wider molecular level. tubes are formed from multiple cells whose lateral surfaces bind to each other via adherens and tight junctions to main- Wrapping: An individual cell can form a tubule of defined tain the patency of the lumen (Figure 1A). The smallest tubes luminal diameter by wrapping its plasma membrane around – are unicellular, made up of single cells (Figure 1, B D). Tubes an extracellular core of matrix or other material and forming are often dynamic and can convert from one type to another an autocellular junction (AJ) or “seam” to itself (Figure 1B). during development (Ribeiro et al. 2004; Denker et al. 2013; Seamed unicellular tubes are generally open at both ends. Lenard et al. 2013). Cells within tubes can also delaminate, Examples of seamed unicellular tubes include the C. elegans change identity, and give rise to other cell types (Kalluri and excretory pore cell (Nelson et al. 1983); Drosophila tracheal Weinberg 2009; Zuryn et al. 2012). Biological tubes make up stalk cells, which wrap around a core of chitin (Ribeiro et al. a vast proportion of cells in all eukaryotic organisms, and 2004; Tonning et al. 2005; Luschnig et al. 2006); many ver- tube abnormalities underlie many birth defects and diseases tebrate capillaries (Yu et al. 2015), especially in the brain in humans, yet the mechanisms that determine tubule iden- (Bär et al. 1984); and many invertebrate glial socket cells tity, size, shape, and connectivity are incompletely under- that wrap around neurons (Freeman 2015; Shaham 2015). stood (Lubarsky and Krasnow 2003; Iruela-Arispe and Beitel A related topology is observed in other wrapping glia, such as 2013; Sigurbjornsdottir et al. 2014). mammalian Schwann cells, which do not form actual junc- The Caenorhabditis elegans excretory system is a very sim- tion seams, but instead adhere to themselves via secreted ple tubular organ that consists of just three unicellular tubes myelin (Simons and Trotter 2007; Jessen et al. 2015). (canal, duct, and pore) connected in tandem to form a con- tinuous lumen (Nelson et al. 1983) (Figure 2). Dynamic Wrapping and autofusion: A seamed tube formed by wrap- changes in pore identity and tube connectivity occur during ping can subsequently autofuse to eliminate the autocellular development (Figure 3, Figure 4). Two fused gland cells junction and become a “seamless” tube that has no junctions (Figure 3E) form a syncytium attached to the canal–duct running along its length (Figure 1C). Autofusion occurs in the junction (Nelson et al. 1983), and two canal-associated neu- C. elegans excretory duct (Stone et al. 2009) and pharyngeal rons (Figure 2A, Figure 3F) have axons that run along the valve cells (Rasmussen et al. 2008), some capillaries in the basal surface of the canal cell and have been proposed to zebrafish vascular system (Lenard et al. 2015), and mamma- regulate canal function (Hedgecock et al. 1987; Forrester lian Madin-Darby canine kidney (MDCK) cells grown and Garriga 1997). The system appears to function in both on micropillar arrays in culture (Sumida and Yamada osmoregulation and secretion, and it shares many molecular 2013, 2015). features with osmoregulatory or renal systems in other or- ganisms, and with other epithelial and endothelial tube net- Hollowing: As an alternative to cell wrapping, a single cell can works. The simplicity of the excretory system, and its create a seamless tube through “cell hollowing,” in which amenability to genetic analysis and live imaging, make it a endocytic (plasma membrane-derived) and/or exocytic very attractive model for studying the cell biology of (Golgi-derived) vesicles coalesce to form an internal apical tubulogenesis, tube dynamics, and other aspects of organ surface that connects to the plasma membrane (Figure 1D). development and physiology. This mechanism was first described in mammalian endothe- lial cells grown in culture (Folkman
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