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Epithelial Shaping by Diverse Apical Extracellular Matrices Requires the Nidogen Domain Protein DEX-1 in Caenorhabditis Elegans

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Epithelial Shaping by Diverse Apical Extracellular Matrices Requires the Nidogen Domain Protein DEX-1 in Caenorhabditis Elegans | INVESTIGATION Epithelial Shaping by Diverse Apical Extracellular Matrices Requires the Nidogen Domain Protein DEX-1 in Caenorhabditis elegans Jennifer D. Cohen,* Kristen M. Flatt,† Nathan E. Schroeder,†,‡ and Meera V. Sundaram*,1 *Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104 and †Program in Neuroscience and ‡Department of Crop Sciences, University of Illinois at Urbana-Champaign, Illinois 61801-4730 ORCID IDs: 0000-0003-3327-2136 (N.E.S.); 0000-0002-2940-8750 (M.V.S.) ABSTRACT The body’s external surfaces and the insides of biological tubes, like the vascular system, are lined by a lipid-, glycoprotein-, and glycosaminoglycan-rich apical extracellular matrix (aECM). aECMs are the body’s first line of defense against infectious agents and promote tissue integrity and morphogenesis, but are poorly described relative to basement membranes and stromal ECMs. While some aECM components, such as zona pellucida (ZP) domain proteins, have been identified, little is known regarding the overall composition of the aECM or the mechanisms by which different aECM components work together to shape epithelial tissues. In Caenorhabditis elegans, external epithelia develop in the context of an ill-defined ZP-containing aECM that precedes secretion of the collagenous cuticle. C. elegans has 43 genes that encode at least 65 unique ZP proteins, and we show that some of these comprise distinct precuticle aECMs in the embryo. Previously, the nidogen- and EGF-domain protein DEX-1 was shown to anchor dendrites to the C. elegans nose tip in concert with the ZP protein DYF-7. Here, we identified a new, strong loss-of-function allele of dex-1, cs201. dex-1 mutants die as L1 larvae and have a variety of tissue distortion phenotypes, including excretory defects, pharyngeal ingression, alae defects, and a short and fat body shape, that strongly resemble those of genes encoding ZP proteins. DEX-1 localizes to ZP-containing aECMs in the tissues that show defects in dex-1 mutants. Our studies suggest that DEX-1 is a component of multiple distinct embryonic aECMs that shape developing epithelia, and a potential partner of multiple ZP proteins. KEYWORDS C. elegans; extracellular matrix; zona pellucida; cuticle; excretory system PICAL extracellular matrices (aECMs) line exposed ep- fixation conditions (Chappell et al. 2009; Luschnig and Uv Aithelial surfaces, such as the epidermis and the insides of 2014). It is clear that aECMs are lipid-, glycoprotein-, and tubes. For example, the stratum corneum lines the outside of glycosaminoglycan-rich structures that often form distinct the skin (Feingold 2007), a glycocalyx lines the inside of layers (Chappell et al. 2009; Johansson et al. 2013; Gill blood vessels (Reitsma et al. 2007), and surfactant coats et al. 2016). Despite the importance of aECMs, individual the inside of lung alveoli (Pérez-Gil 2008). aECMs serve as aECM components’ functions, and their relationships with primary barriers to infectious agents and have important other components, are often poorly described. roles in tissue shaping and integrity (Plaza et al. 2010; Zona pellucida (ZP) proteins can be found in high abun- Johansson et al. 2013; Tarbell and Cancel 2016). However, dance in many apical matrices (Plaza et al. 2010). For exam- aECMs are poorly characterized relative to stromal ECMs or ple, the founding members of the family, ZP1, ZP2, and ZP3, basement membranes, in part due to their fragility under are found in the mammalian egg-coat, the ZP, where they both enable fertilization and serve as a barrier to polyspermy Copyright © 2019 by the Genetics Society of America doi: https://doi.org/10.1534/genetics.118.301752 (Gupta 2018). Other ZP proteins are found in the lumen Manuscript received September 13, 2018; accepted for publication November 5, 2018; of the vascular system [endoglin and betaglycan (ten Dijke published Early Online November 8, 2018. Supplemental material available at Figshare: https://doi.org/10.25386/genetics. et al. 2008)], the kidney tubules [uromodulin and oit3 7312148. (Zaucke et al. 2010; Yan et al. 2012)], or in the tectorial 1 Corresponding author: Department of Genetics, University of Pennsylvania membrane of the inner ear [tectorins (Legan et al. 1997)]. Perelman School of Medicine, 446a Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA 19104-6145. E-mail: [email protected] Loss or dysfunction of these ZP proteins can cause hereditary Genetics, Vol. 211, 185–200 January 2019 185 hemorrhagic telangiectasia (HHT), chronic kidney disease, et al. 2017). Finally, LET-653 maintains the tiny excretory or deafness, respectively (Rampoldi et al. 2011; Richardson duct tube during its elongation. The unicellular duct tube is et al. 2011; Saito et al. 2017). In invertebrates such as the middle tube of the C. elegans excretory system, which is Caenorhabditis elegans and Drosophila, various ZP proteins required for osmoregulation (Nelson et al. 1983; Nelson and are part of the cuticle or exoskeleton (Sebastiano et al. Riddle 1984). During embryogenesis, the duct tube elongates 1991; Muriel et al. 2003; Sapio et al. 2005; Fernandes et al. from a simple toroid to a more complex shape with a looped 2010). While some ZP proteins are involved in signaling via lumen (Sundaram and Buechner 2016). In let-653 mutants, protein–protein interactions, others polymerize to form ma- the duct lumen fragments and develops dilations (Gill et al. trix fibrils with presumed structural roles (Jovine et al. 2002; 2016). LET-653 is also required for proper morphogenesis of Bokhove et al. 2016; Saito et al. 2017). Better understanding cuticular alae in L1 larvae and adults (Gill et al. 2016; of how ZP-containing matrices shape tissues will require Forman-Rubinsky et al. 2017). Here, we determined that identification of other components of these matrices. these different ZP mutant phenotypes can be explained in The nematode Caenorhabditis elegans contains multiple part by nonuniform tissue distributions of different embry- different types of aECMs, and is a tractable model system onic ZP proteins, thereby defining a diverse set of precuticu- for studying aECM composition, assembly,and function. Most lar aECMs. external surfaces of larvae and adults are lined by a cuticle We sought new mutants with ZP-like phenotypes and composed primarily of collagens (Page and Johnstone identified a new allele of the previously described gene dex- 2007), with different ZP proteins termed cuticlins (CUT pro- 1. DEX-1 is a proposed partner of the ZP protein DYF-7 in a teins) contributing to stage-specific lateral ridges or alae dendritic cap matrix that anchors sensory dendrites and glia (Sebastiano et al. 1991; Muriel et al. 2003; Sapio et al. to the nose tip (Heiman and Shaham 2009; Low et al. 2018). 2005). In contrast, the pharynx or foregut is lined by a dif- In both dex-1 and dyf-7 mutants, dendrites retract into the ferent type of cuticle containing the polysaccharide chitin body cavity under tension from elongation forces in the em- (Zhang et al. 2005), and internal epithelia such as the gut bryo. dex-1 encodes a nidogen- and EGF-domain transmem- are not lined by cuticle, although their alternative aECMs brane protein related to the conserved basement membrane have not yet been described. Finally, in the embryo, cuticles protein nidogen and to other mammalian matrix proteins are not secreted until the completion of epidermal elongation including alpha-tectorin, MUC4, and SNED1. Here, we show and morphogenesis, and epithelial tissue development oc- that DEX-1 localizes to diverse ZP-containing aECMs in the curs in the context of a still ill-defined precuticular or embryo and to L1 cuticle alae. The originally described dex-1 “sheath” matrix (Priess and Hirsh 1986). Multiple ZP pro- allele leaves the nidogen and EGF domains intact and is hy- teins, including FBN-1, NOAH-1, NOAH-2, and LET-653, pomorphic. By characterizing a new, stronger allele that dis- are components of this early precuticular matrix, and play rupts those domains, we show that DEX-1 is important for a important roles in embryonic tissue shaping (Kelley et al. variety of aECM-dependent tissue shaping processes in the 2015; Gill et al. 2016; Vuong-Brender et al. 2017). Other embryo. DEX-1 is not normally expressed beyond the L1 lar- apparent components of this early matrix include mem- val stage, but in the accompanying manuscript (Flatt et al., bers of the extracellular leucine-rich repeat only (eLRRon) 2019), we show that starvation signaling upregulates DEX-1 (Mancuso et al. 2012) and lipocalin (Forman-Rubinsky to remodel cuticle structure and generate alae in dauer lar- et al. 2017) families, which also play important roles in the vae. Together, our studies suggest that DEX-1 is a component shaping or protection of mammalian tissues (Paragas et al. of diverse aECMs and shapes tissues in concert with many 2012; Chen and Birk 2013), suggesting similarities between different C. elegans ZP proteins. the C. elegans precuticular matrix and ECMs of other organ- isms. Such similarities make this early matrix of particular interest. Materials and Methods C. elegans has several advantages for studying aECM. First, Worm strains, alleles, and transgenes aECM components can be easily visualized in live animals using fluorescent fusion proteins, avoiding typical aECM de- All strains were derived from Bristol N2 and were grown at struction by fixation. Second, unbiased genetic screening ap- 20° under standard conditions (Brenner 1974). dex-1 mu- proaches can be used to identify new matrix components. tants were obtained from mothers rescued with a dex-1(+) Foundational studies on ZP components of the aECM suggest transgene or homozygous for dex-1. Mutants used included: some of the phenotypes that we would expect to see in new dex-1(ns42)I(Heiman and Shaham 2009), dex-1(cs201) precuticle matrix mutants. For example, FBN-1 anchors the I (this study), fbn-1(ns283) III (Kelley et al.
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