RIKEN Center for Developmental Biology, Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
* Author for correspondence (e-mail: takeichi{at}cdb.riken.go.jp)
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Summary |
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Key words: Fat, Cadherin, Cell-cell interaction, Actin dynamics
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Introduction |
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The Fat subfamily of cadherins is conserved from flies to mammals (Fig. 2). The first gene identified, Drosophila fat, was cloned in 1991 and shown to encode an unusually large transmembrane molecule containing 34 cadherin repeats (Mahoney et al., 1991). In recent years, several other members of the Fat subfamily have been reported to exist in both invertebrates and vertebrates (Dunne et al., 1995
; Ponassi et al., 1999
; Cox et al., 2000
; Mitsui et al., 2002
; Nakayama et al., 2002
). They commonly have 34 cadherin repeats, one or two laminin A-G domains and several epidermal growth factor (EGF) motifs in their extracellular regions. There are two Fat cadherins in Drosophila, Fat and Fat-like. Vertebrates have four Fat cadherins: Fat-J, Fat1, Fat2 and Fat3. From overall sequence similarity, Fat cadherins can be roughly divided into two subfamilies: one comprises Fat and Fat-J; and the other includes Fat-like, Fat1, Fat3 and Fat2 (Fig. 3). These may be the largest molecules regulating cell-cell interactions. Their huge molecular masses (about 500-600 kDa) have hindered studies of the molecular aspects of their roles. Nevertheless, recent efforts have shed light on their molecular and cellular functions.
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Fat cadherins in Drosophila |
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Recent studies have focused on the role of Fat in the regulation of PCP (Fanto and McNeill, 2004) (Fig. 4). Some classes of epithelial cell display a polarity in the plane of epithelium, a feature referred to as PCP. PCP is observed in many organs across species, including wing hairs and ommatidia of Drosophila, and hairs and stereocilia of mammals. In Drosophila eyes, the ommatidia in fat mutant clones exhibit reversed dorsal-ventral (D/V) polarity (Yang et al., 2002
). PCP in the Drosophila eye is achieved by groups of cells the ommatidial clusters that must act as a single unit. Specification of R3 and R4 cells in the ommatidial cluster determines the orientation of ommatidial rotation in the plane of the epithelium. In contrast to mutations in core PCP components, such as Frizzled, a fat mutation does not affect the specification of R3 and R4 cells, indicating that Fat is not a core PCP component. In PCP regulation, Fat is proposed to be upstream of Frizzled and downstream of Four-jointed and Dachsous (Strutt and Strutt, 2002
; Yang et al., 2002
; Ma et al., 2003
; Matakatsu and Blair, 2004
; Strutt et al., 2004
) (Fig. 4). How Fat regulates Frizzled activity is currently unknown. Four-jointed is a type II transmembrane protein mainly localized in the Golgi apparatus (Strutt et al., 2004
) and is thought to modulate the activity of Fat and Dachsous in this organelle (Clark et al., 1995
). Dachsous regulates Fat activity through its cadherin repeats (Matakatsu and Blair, 2004
). Although Dachsous and Four-jointed might regulate Fat in the PCP pathway, its function as a tumor suppressor might be independent of them, because both Dachsous and Four-jointed mutants show no defect in proliferation of imaginal discs (Clark et al., 1995
; Villano and Katz, 1995
).
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Recently, a second Drosophila Fat subfamily cadherin, Fat-like, was identified (Castillejo-Lopez et al., 2004). Fat-like is expressed in salivary glands and tracheal cells at the embryonic stage. The protein localizes to the apical portion of the epithelia. Knocking down of Fat-like by RNA interference (RNAi) results in abnormal development of tubular structures, such as small deletions or complete lack of the trachea, proventriculus, hindgut and salivary glands. Thus, Fat-like is required for morphogenesis and maintenance of tubular structures of ectodermal origin. In contrast to loss of Fat, loss of Fat-like does not result in overgrowth phenotypes, which indicates that its function might have diverged from that of Fat. No other Fat cadherins besides Fat and Fat-like exist in the Drosophila genome (Hill et al., 2001
).
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Fat cadherins in vertebrates |
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Fat1 regulates actin dynamics and cell-cell contacts |
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We and others have identified Ena/VASP proteins as binding partners of Fat1 (Moeller et al., 2004; Tanoue and Takeichi, 2004
). This family of proteins regulates the actin cytoskeleton by antagonizing capping proteins and/or by increasing the rate of dissociation of the branched junctions on actin filaments at the cell periphery, focal adhesions or cell-cell contact sites (Bear et al., 2002
; Krause et al., 2002
; Renfranz and Beckerle, 2002
; Samarin et al., 2003
). There are three members of the Ena/VASP family in mammals: Mena, VASP and Ena-VASP-like (Evl) (Reinhard et al., 1992
; Gertler et al., 1996
). These are thought to play redundant roles in regulating actin dynamics. Each comprises three domains: an N-terminal EVH1 domain; a proline-rich central domain; and a C-terminal EVH2 domain. Through the EVH1 domain, Ena/VASP proteins interact with several cell-surface receptors and adaptor molecules, such as Sema6A, Robo, vinculin, zyxin, Fyb/slap, lamellipodin and RIAM, all of which regulate the actin cytoskeleton (Krause et al., 2002
; Renfranz and Beckerle, 2002
; Krause et al., 2004
; Lafuente et al., 2004
). Several Src-homology 3 (SH3)-domain-containing proteins bind to the central proline-rich domain, and Ena/VASP proteins associate with actin through the EVH2 domain.
Fat1 has three potential EVH1-binding sites in its cytoplasmic portion and binds to Ena/VASP proteins through these sites (Moeller et al., 2004; Tanoue and Takeichi, 2004
). Moreover, it colocalizes with Ena/VASP proteins at early cell-cell contact sites, lamellipodial edges and filopodial tips. This Fat1-Ena/VASP system appears to be involved in formation of the junctional actin cytoskeleton at early cell-cell contacts: in Fat1-knockdown PAM212 cells, VASP no longer accumulates at these sites, and the junctional actin cytoskeleton does not form properly. Similarly, in Fat1-knockdown NRK-52E cells, the amount of VASP protein accumulating at the leading edges is significantly reduced. The Fat1-Ena/VASP system thus seems to have an important role in regulation of actin dynamics by Fat1 (Fig. 5). However, the phenotypes of Fat1-knockdown cells cannot be explained solely in terms of dysfunction of Ena/VASP proteins. There might be other signaling pathways downstream of Fat1. Fat1 has several proline-rich sequences and a PDZ-domain-binding motif. Identification of molecules interacting with these sites should help us to understand all of the functions of Fat1. Ena/VASP-binding sequences are not found in other Fat family members, which suggests that the regulation of Ena/VASP proteins might be a unique function of Fat1.
Fat1-knockout mice exhibit perinatal lethality, probably caused by loss of glomerular slit junctions (Ciani et al., 2003). Glomerular epithelial cells (podocytes) show an interesting profile of development. At the early embryonic stage, the cells have a polarized morphology, in which ZO-1 protein, a component of the tight junction, is apically localized. The apical junctions then move to the basal portion of the cells and, from these portions, actin-rich cellular processes called foot processes form. Between the foot processes of adjacent cells, a 40-50 nm cell-cell junction called the slit junction, is organized. This functions as the filter of the kidney. Fat1 localizes to slit junctions (Inoue et al., 2001
); indeed, in the Fat1-knockout glomeruli, the slit junctions are absent. In addition, holoprosencephaly and anopthalmia are observed in Fat1-knockout mice (Ciani et al., 2003
). In rare cases, cyclopia is also found. These abnormalities, generally called midline defects, might be caused by defective cell-cell interactions in early developmental stages, but the precise roles of Fat1 in these processes remain to be investigated. Partial redundancy with Fat3 might explain the relatively mild phenotypes of the Fat1-knockout mice.
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Fat2, Fat3 and Fat-J |
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Fat3 is mainly expressed in the central nervous system, especially in the spinal cord (Mitsui et al., 2002). Its sequence most resembles that of Fat1, especially in the cytoplasmic portion, which suggests that its function overlaps that of Fat1. Human Fat-J was identified in a computer-based search for unidentified cadherin molecules (Hong et al., 2004
). It was predicted to have 17 rather than 34 cadherin repeats. However, rat Fat-J is predicted to have 34 cadherin repeats. The true number of cadherin repeats of Fat-J should therefore be determined in future studies. Because Fat-J most resembles Drosophila Fat, whether it regulates cell proliferation and PCP, as Drosophila Fat does, is an interesting question. Mammalian orthologs of Dachsous and Four-jointed have recently been identified (Ashery-Padan et al., 1999
; Nakajima et al., 2001
; Hong et al., 2004
). We must therefore clarify the relationship between the three molecules in mammals.
Fat1, Fat2, Fat3 and Fat-J are present in the genomes of chick, zebrafish and Fugu. The sequence of each of these is well conserved among vertebrate species, which suggests their functions are also conserved. However, as mentioned above, the degree of similarity shared by the vertebrate and invertebrate Fat cadherins is low; therefore, it is possible that the vertebrate molecules have acquired roles different from those of invertebrate Fat cadherins.
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Conclusions and perspectives |
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Acknowledgments |
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References |
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