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Assembly and Disassembly of Brush Borders Driven by Villin, a Unique Bundling/Severing Actin-Binding Protein

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Assembly and Disassembly of Brush Borders Driven by Villin, a Unique Bundling/Severing Actin-Binding Protein Gastrointestinal Functions, edited by Edgard E. Delvin and Michael J. Lent?e. Nestle Nutrition Workshop Series. Pediatric Program. Vol. 46. Nestec Ltd.. Vevey/Lippincott Williams & Wilkins. Philadelphia <i'< 2001. Assembly and Disassembly of Brush Borders Driven by Villin, a Unique Bundling/Severing Actin-Binding Protein Sylvie Robine, Evelyne Ferrary, Alexandre Lapillonne, and Daniel Louvard CNRS UMR 144, Institut Curie, Paris, France Digestive processes involve several organs composed of highly specialized epithe- lial cells. Despite a great diversity of function, all epithelial cells along the digestive tract have certain common structural and functional features. These cells display a unique organization that reflects their particular specialized roles in transport, endocytosis, or transcytosis. These functions contribute to the generation of steep concentration gradients of nutrients and electrolytes between the external and the internal milieus of the body. The ability of this epithelium to create an asymmetric chemical gradient between the fluid bathing its luminal membrane and the basolateral membrane in contact with the internal milieu can be explained by an asymmetric distribution of membrane-bound enzymes and transporting systems between these membranes. The cellular architecture that contributes to the functional polarity of these cells implies the existence of distinct domains of the plasma membrane and a specialized cytoskeletal matrix associated with membrane domains. The polarized distribution of cellular components is achieved in the course of terminal differentia- tion and is maintained after this event. At their apical borders facing the external milieu, epithelial intestinal cells possess a unique organelle, the brush border. The brush border provides a greatly expanded surface that facilitates absorption of digestion products. It is composed of thousands of stiff microvilli containing bundles of microfilaments made of actin, associated with actin-binding proteins (ezrin, fimbrin, brush border myosin I, espin, and villin). Among these proteins, villin shows special features suggesting that it plays a key role in the dynamics of the brush border. In this chapter recent advances in the understanding of the brush border assembly and the role of villin in the reorganization of this organelle are described. ORGANIZATION OF THE BRUSH BORDER CYTOSKELETON Proteins of the Brush Border Cytoskeleton The brush border of absorptive epithelial cells is composed of the microvilli and the terminal web (Fig. 1). In the core of each microvillus is a bundle of 20 specialized 23 24 ASSEMBLY AND DISASSEMBLY OF BRUSH BORDERS l! II FIG. 1. Transmission electron microscopy of the luminal half of an epithelial cell of mouse small intestine, x 16,000. (Micrograph obtained from G. Pehau-Amaudet, UMR 144, CNRS- Institut Curie, Paris, France.) actin filaments that play a structural role, maintaining the shape of the microvillus. The (+) ends of these microfilaments point toward the site of membrane insertion at the tip of the microvillus in a dense structure that is not well characterized (1) (Fig. 2). The rootlets of the bundles are connected to the terminal web by another actin complex that also contains myosin II and nonerythroid spectrin proteins (2). The microvillus core bundles are assembled by a specific set of proteins that are important in generating their rigid structure. Each microvillar protein belongs to a family of proteins (Table 1). Many of the component proteins have been identified and cloned, and their function in vitro has been studied in detail. These proteins can be classified as proteins that cross link actin filaments to form bundles (villin, I- fimbrin, and espin) or proteins that link actin filaments to the plasma membrane (brush border myosin I, and ezrin) (Fig. 2, Table 1). The protein villin is one the major proteins that cross links the actin filaments to form bundles in a ratio of one villin molecule to 10 actin monomers. This protein, ASSEMBLY AND DISASSEMBLY OF BRUSH BORDERS 25 HI ACTIN • VILLIN O I-FIMBRIN O ESPIN BBM1/ Calmodulin ^ EZRIN FIG. 2. Schematic localization of the major proteins of the brush border cytoskeleton. which bundles actin filaments in a Ca+ +-dependent manner, is described in detail below. The effect of Ca+ + on the length of the microvillar core is thought to be physiologically important. As an actin cross-linking protein, fimbrin also forms tightly packed parallel actin bundles by binding actin filaments in a ratio of one fimbrin molecule to 10 actin monomers. Among the three isoforms of fimbrin (L-, T-, and I-fimbrin), intestinal epithelial cells express a unique fimbrin isoform, I- fimbrin (3). Espin, a recently discovered third actin-bundling protein, is estimated to be present in a ratio of one espin molecule for every 130 actin monomers (4). Another actin-binding protein, brush border myosin I, forms in association with calmodulin the cross bridges that tether actin bundles to the inner surface of the plasma membrane. Ezrin distribution is not restricted to cells with well-organized brush borders, differing in this respect from villin, brush border myosin I, and I- fimbrin. Together with radixin and moesin, ezrin belongs to the ERM (ezrin/radixin/ moesin) subfamily of the band 4.1 protein superfamily. Thus, it has been proposed that ezrin plays a role in linking the microfilaments to the plasma membrane (5). All these proteins that are involved in the organization of the brush border cyto- skeleton are highly conserved among species. They are all expressed in the brush border of mature enterocytes but have different patterns of expression during em- bryogenesis. Assembly of the Intestinal Microvilli During differentiation of the intestine, the epithelium undergoes a transition from a simple epithelium, the surface of which is sparsely covered by short and irregular 26 ASSEMBLY AND DISASSEMBLY OF BRUSH BORDERS TABLE 1. Properties of microvillar cytoskeletal proteins of intestinal cells Molecular weight In vitro Protein (kd) activities Ligands Family proteins Localization Villin 92.5 Capping F/G Actin Advillin Epithelial cells of Nucleating Ca^ Supervillin the urogenital Severing PiP2 Protovillin and digestive Bundling Quail gene product tracts Dematin Gelsolin Severin Fragmin l-fimbrin 68 Bundling F-actin L/T-fimbrin/plastin Brush borders of Ca^, Mg++ Dystrophin intestinal and Spectrin/fodrin kidney cells a-actinin Filamin ABP 120 BBM1 110 Mechano F-actin Myosins la Brush borders of enzyme Mg^ absorptive cells ATP Phospholipids Calmodulin Ezrin 67 Linking the F-actin Radixin Epithelial cells microfilaments PiP2 Moesin to the plasma CD44/rho-GDI Merlin/schannomin membrane CD43 EM 1PTPH1 I-CAM PTPase MEG PKA Band 4.1 EBP50 Talin RhoGDI Espin 30 Bundling F-actin Espin 110 kd Brush borders of Forked protein intestinal and kidney cells BBMI, brush border myosin I. microvilli, to a mature epithelium covered by the densely packed microvilli of the brush border. This morphologic change is essential for the highly efficient absorptive function of the intestine. Assembly of the brush border initially occurs during villus morphogenesis. In human fetuses, short and irregularly placed microvilli cover the epithelial cells during the late second and early third fetal months (6,7). Subse- quently, short and regular microvilli fill the apical surface. Although the course of microvillus assembly has not been carefully examined in human fetal intestines, it has been studied in detail in developing mouse and chicken intestine (2). It is likely that human brush borders are generated in the same manner. How are these different components assembled to form a microvillus? Analysis of the pattern of gene expression encoding for these proteins and of the proteins during embryogenesis and, in the adult, along the crypt-villus axis reveals that this structure is not autoassembled. Assembly of the microvillus core is strictly regulated, ASSEMBLY AND DISASSEMBLY OF BRUSH BORDERS 27 both spatially and temporally (8-14). All proteins are present in the cytoplasm before being localized to the apical surface of the cells. Ezrin is already produced in oocyte and is present throughout preimplantation of the embryo, long before a rudimentary gut is formed. Before compaction, ezrin is located at the cell cortex. It becomes restricted to the apical microvilli of the outer cells and remains there until after cell stages 8-16 (15). Thus, ezrin localization to the microvilli is correlated with cell polarization. During mouse embryogenesis, intestinal epithelium maturation is char- acterized by a transition from a thick pseudostratified structure to simple columnar cells (from embryo day 11 to day 15, depending on the intestinal segments). Ezrin has already appeared in the pseudostratified epithelium by day 10 (Fontaine JJ, personal communication, 1998). The apical localization of ezrin precedes that of villin. Villin localizes at the apex of cells when rudimentary microvilli appear on the surface at 12.5 days (8,10-13). Fimbrin isoforms are sequentially switched on and off during development (14). L- and T-fimbrin, the two nonintestinal epithelial cell isoforms, are first produced by 10.5 days. Whereas T-fimbrin is predominantly Microvilli formation detection of villin, detection ezrin L-, T-fimbrin, I-fimbrin BBM1 of ezrin apical andBBMl apical apical apical 0 10 12 14 16 18 20 incubation days post-hatch previllous ridge formation Terminal web formation Detection of myosin Detection of and fodrin. TW 260/240
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