Department of Cell Biology, Institute of Anatomy, University of Aarhus, DK-8000 Aarhus C, Denmark
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ABSTRACT |
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The multiligand, endocytic receptors megalin and cubilin
are colocalized in the renal proximal tubule. They are heavily
expressed in the apical endocytic apparatus. Megalin is a 600-kDa
transmembrane protein belonging to the low-density lipoprotein-receptor
family. The cytoplasmic tail contains three NPXY motifs that mediate
the clustering in coated pits and are possibly involved in signaling functions. Cubilin, also known as the intestinal intrinsic
factor-cobalamin receptor, is a 460-kDa receptor with no transmembrane
domain and no known signal for endocytosis. Because the two receptors
bind each other with high affinity and colocalize in several tissues, it is highly conceivable that megalin mediates internalization of
cubilin and its ligands. Both receptors are important for normal tubular reabsorption of proteins, including albumin. Among the proteins
normally filtered in the glomeruli, cubilin has been shown to bind
albumin, immunoglobulin light chains, and apolipoprotein A-I. The
variety of filtered ligands identified for megalin include vitamin-binding proteins, hormones, enzymes, apolipoprotein H, albumin,
and 2- and
1-microglobulin. Loss of these
proteins and vitamins in the urine of megalin-deficient mice
illustrates the physiological importance of this receptor.
proteinuria; vitamin D; vitamin B12; retinol; low-density lipoprotein- receptor family
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INTRODUCTION |
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MEGALIN IS A MULTILIGAND, endocytic receptor belonging to the low-density lipoprotein (LDL)-receptor family. It is heavily expressed in the renal proximal tubule. A long list of ligands for megalin has been identified establishing an important role for the tubular uptake of filtered proteins. Among the ligands are vitamin binding proteins and several hormones, suggesting an additional role of megalin in the metabolism and homeostasis of essential vitamins, including vitamin D, as well as calcium.
Cubilin, also known as the intestinal intrinsic factor-cobalamin receptor, is coexpressed with megalin in the renal proximal tubule. Although structurally very different from megalin, it has many similar features, being a multiligand, endocytic receptor sharing several ligands with megalin and being important for the tubular reabsorption of proteins. In addition, megalin has been shown to bind cubilin and is most likely involved in the endocytosis of this receptor.
The present review will focus on megalin and cubilin in the kidney, their structural features, mutual interaction, potential signaling function, and their role in tubular protein reabsorption, vitamin metabolism, as well as calcium homeostasis.
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HISTORY |
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Megalin
Megalin was originally identified as the antigen in Heymann nephritis of rats. It was purified from rat kidney brush border and named gp330 on the basis of molecular weight as estimated by its mobility during gel electrophoresis (43). Megalin was localized in the apical endocytic pathway of renal proximal tubule as well as in the glomeruli (43). Later, it was identified in several other epithelia (for a recent review, see Ref. 16). Many proteins were identified as ligands, including receptor-associated protein (RAP), lipoproteins, enzymes, and enzyme inhibitors, suggesting the role of megalin as a scavanger endocytic receptor. In 1994, the protein was cloned by Saito et al. (81), showing it to be a 600-kDa glycoprotein and suggesting the name "megalin." In 1996, megalin-deficient mice was produced by gene targeting by Willnow et al. (92), adding significant new information about the important role of this receptor.Cubilin
Cubilin was identified as the target of teratogenic antibodies produced by the injection of renal brush-border preparations into rabbits (78). It was named gp280 on the basis of the estimated molecular weight and localized to the apical endocytic apparatus of renal proximal tubule and the visceral epithelia of yolk sac (78). No ligands were identified until 1997, when gp280 was shown to be identical to the intestinal intrinsic factor-cobalamin receptor (84). Also, in 1997 RAP was shown to be a ligand for cubulin, followed by several other proteins. The receptor was cloned by Moestrup et al. (65) in 1998 and shown to be a 460-kDa glycoprotein with no apparent cytoplasmic domain, and the name "cubilin" was suggested on the basis of its structure dominated by complement subcomponents C1r/C1s, Uegf, and bone morphogenic protein-1 (CUB) domains. ![]() |
STRUCTURE |
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Megalin
Megalin is an ~4,600-amino acid transmembrane protein (Fig. 1) with a large NH2-terminal extracellular domain, a single transmembrane domain, and a short cytoplasmic tail (81). The protein belongs to the LDL-receptor family (76), sharing common features with the following mammalian receptors including the LDL receptor, the LDL-receptor-related protein (LRP), the very-low-density lipoprotein (VLDL) receptor, and the apolipoprotein E (apo E) receptor-2 (reviewed in Ref. 29). Both rat (81) and human (37) megalin has been cloned, and the nonglycosylated molecular mass is estimated to 517 kDa (81). The cytoplasmic tail contains three NPXY motifs mediating the binding to adaptor proteins and the clustering into coated pits. In addition, this motif may serve signaling functions (75). Also, the cytoplasmic domain contains several Src homology 3 and one Src homology 2 recognition sites (37). The extracellular domain contains four cystein-rich, complement-type repeats, probably constituting the ligand binding regions separated by epidermal growth factor (EGF) precursor homology domains containing YWTD repeats responsible for the pH-dependent release of ligands (24). The human megalin gene has been located to chromosome 2q24-q31 (46).
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Cubilin
Cubilin is an ~3,600-amino acid protein with no transmembrane domain (Fig. 1). The complete DNA sequences of rat (65), human (52), and canine (96) cubilin have been identified, showing a nonglycosylated molecular mass of 400 kDa. It has little structural homology with other known endocytic receptors. The extracellular domain contains 27 CUB domains. The CUB domains most likely constitute the ligand binding domains, and the binding site for intrinsic factor-cobalamin has been located within CUB domains 5-8 whereas the binding site for RAP is located within CUB domains 13-14 (54). The CUB domains are preceded by a stretch of 110 amino acids followed by 8 EGF-type repeats. The initial amino acid stretch contains a furin cleavage site, which may indicate proteolytic processing in the trans-Golgi network (52). The NH2-terminal region seems essential to membrane anchoring of the protein. This segment contains an amphipatic helix structure with some similarity to the lipid binding regions of apolipoproteins, which may contribute to the anchoring of the receptor in the membrane (54). The human cubilin gene has been located to chromosome 10p12.33-p13 (52). ![]() |
EXPRESSION AND SYNTHESIS |
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Megalin
Megalin is expressed in many epithelial cells (49, 99; recently reviewed in Ref. 16), in particular absorptive epithelia facing transcellular fluids, such as the renal proximal tubule, the glomerular podocytes, the choroid plexus, ependymal cells, epididymis, thyroid cells, labyrinthic cells of the inner ear, and the ciliary epithelium of the eye. In addition, megalin is expressed in the visceral yolk sac, type II pneumocytes, the parathyroid hormone (PTH)-secreting cells of the parathyroid gland, the small intestine, the endometrium, the oviduct, and the cytotrophoblast of the placenta. Megalin has also been identified in embryonic tissues such as the trophoectodermic cells and the neuroectoderm (32, 80). During renal development, megalin can be identified in the mesonephros, the nephronic vesicle, and the ureteric bud (80). Megalin is expressed in the S-shaped body later giving rise to both the glomeruli and the proximal as well as the distal tubule. Later during development, megalin is only expressed in the proximal tubules and, to a lesser extent, the glomerulus (80).In the kidney proximal tubule (Fig. 2),
megalin can be localized to the brush border, coated pits, endocytic
vesicles (1, 3, 14, 45), and the membrane recycling
compartment, dense apical tubules (6, 17, 19). The
membrane expression is high in small and large endosomes in the
proximal tubule cells but is virtually absent in late
endosomes/prelysosomes (16). However, smaller amounts of
intact and degraded megalin have been identified in the matrix of the
lysosomes (19). In rats the expression of megalin in the
proximal tubule brush border varies between different segments, with
the highest expression in segment two (19). Megalin has
also been identified in the glomerular podocytes of rat kidney
(44).
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After translation in the rough ER (RER), megalin binds rapidly and with high affinity to the 40-kDa protein RAP. RAP also binds other members of the LDL-receptor family and serves as a chaperone protecting newly synthesized receptor from the early binding of ligands (12, 13, 90, 94). In addition, RAP may be involved in the folding of the receptors (13). RAP deficiency is associated with a significant decrease in the expression as well as a subcellular redistribution of megalin in the proximal tubule (10). A HNEL motif, serving as an RER-retention signal, is present in RAP, and the protein is predominantly located in this organelle (12). Thus RAP is a predominantly intracellular ligand for megalin. However, due to its high-affinity association with megalin, inhibiting the binding of most other ligands, it has served as an important tool for the study of ligand binding to megalin.
Cubilin
Cubilin is highly expressed in the renal proximal tubule and the visceral yolk sac (79), the epithelium of the small intestine (9, 83), the placental cytothrophoblast (33; for a recent review, see Ref. 16), and possibly other tissues including thymus (33), although at present it seems more restricted than the expression of megalin. In the proximal tubule (Fig. 2), cubilin expression very closely resembles that of megalin represented by the brush border and all constituents of the coated pit endocytic and the membrane recycling pathway (78, 84). Cubilin is also identified in lysosomes (84). Similar to megalin, cubilin is expressed in the S-shaped body during renal development whereas later expression is confined to the proximal tubule only (80). So far it has not been identified in the glomerulus.The posttranslational processing of cubilin may involve furin-mediated cleavage in the trans-Golgi network, as suggested by the finding that affinity-purified human cubilin appears to be truncated at a recognition cleavage site for furin in the NH2-terminal region (52). Furthermore, pulse-chase studies have suggested an unusual processing of cubilin in yolk sac cells, involving the expression of newly synthesized, endoglycosidase H-sensitive cubilin at the plasma membrane although the majority of cubilin is endoglycosidase H resistant (4). This indicates that newly synthesized cubilin is targeted to the plasma membrane and recycled to the Golgi apparatus for final processing, possibly involving both carbohydrate modifications and furin-mediated truncation. Posttranslational processing may be tissue specific, as it was recently shown that ileal cubilin undergoes more extensive NH2-linked glycosylation than renal cubilin (95).
Recently, it was shown that a canine disorder characterized by defective trafficking of cubilin into the apical membranes and a functional cubilin deficiency was not caused by a defect in the cubilin gene. Rather, it was suggested that a yet unknown accessory protein is required for cubilin brush-border expression (96).
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FUNCTION |
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Protein Reabsorption
Megalin was recognized early as a endocytic receptor involved in the tubular uptake of proteins. A large number of ligands have been identified (Table 1). Although not all of these can be expected to be present in the glomerular filtrate, many are recognized markers of defective tubular reabsorption, including vitamin D-binding protein (DBP), vitamin A/retinol-binding protein (RBP),
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Thus structural as well as functional defects in either megalin or cubilin are associated with proteinuria, suggesting both receptors to be essential to normal tubular reabsorption of filtered proteins.
Ligands.
The known ligands for megalin normally filtered in the glomeruli
include DBP, RBP, the vitamin B12/cobalamin plasma carrier protein, transcobalamin (TC)-B12, PTH, insulin, EGF,
prolactin, albumin, 2- and
1-microglobin,
apo H, transthyretin, lysozyme, cytochrome-c,
-amylase,
and Ca2+ (Table 1). Many of these proteins are either
carrier proteins or hormones, suggesting megalin to be involved in the
metabolism of vitamins, and in the renal clearance of many filtered
hormones by endocytic uptake and degradation. In most cases ligand
binding is Ca2+ dependent, and megalin itself binds calcium
very strongly (17). It has been shown by site-directed
mutagenesis analysis that mutations of basic amino acid residues in
aprotinin, a 6-kDa proteinase inhibitor and a ligand for megalin,
decrease the affinity for the receptor, suggesting that binding is
charge dependent and favored by cationic sites on the ligands
(64). However, many ligands are anionic proteins,
indicating that it is the distribution of charge rather than the
overall isoelectric point that is important for binding, as also
suggested previously (20). The binding of almost all
ligands can be inhibited by RAP. This high-affinity binding is
exploited in both the study of receptor function, ligand binding, as
well as for affinity purification of the receptor (66).
Megalin has at least two different binding sites for RAP, as
demonstrated by surface plasmon resonance analysis. Binding of
the first RAP molecule with high affinity was followed by binding of a
second molecule with lower affinity (63).
Megalin-knockout mice. Much of our recent knowledge on the functions of megalin is based partially on data recovered from the study of megalin-deficient mice. These mice, produced by gene targeting, exhibit severe forebrain abnormalities as well as lung defects (92). Most of them die perinatally; however, approximately 1 of 50 survive to adulthood, constituting a model for the study of megalin function (92). The kidneys of these mice are generally normal; however, ultrastructurally the proximal tubule cells are characterized by a loss of apical endosomes (92), coated pits, and recycling dense apical tubules (21). This probably reflects decreased endocytic activity and supports an important general role for megalin in maintaining proximal tubule endocytosis. The megalin-deficient mice excrete an increased amount of a number of low-molecular-weight plasma proteins in the urine. This is a result of defective tubular reabsorption, as shown by the absence of immunodetectable protein ligands in the proximal tubule cells of deficient mice (8, 18, 36, 55, 67, 71). So far, no significant changes in transport of water, electrolytes, glucose, or amino acids have been described in megalin-deficient mice (55).
Receptor-receptor interactions. As discussed previously, the primary sequence of cubilin does not predict a transmembrane domain (65). Thus cubilin itself does not harbor any obvious sites for interaction with adaptor proteins or other mediators of clathrin-coated endocytosis. However, a high-affinity, Ca2+-dependent, and partially (75%) RAP-inhibitable binding between purified cubilin and megalin has been described (65), suggesting that megalin mediates the cointernalization and possibly recycling of cubilin. The binding between megalin and cubilin appears to be complex. However, by fitting the binding data to a one-binding-site model, a dissociation constant of ~7 nM was measured (65). A similar mechanism involving another member of the LDL-receptor family has been suggested for the internalization of the urokinase receptor-bound-urokinase-inhibitor complex (22). This glycophosphatidylinositol-anchored receptor-ligand complex is internalized by binding to LRP. Recently, it was shown in vitro that the uptake of high-density lipoprotein, which binds to cubilin, was inhibited by anti-megalin antibodies as well as by megalin anti-sense oligonucleotides (33). In addition, treatment with megalin anti-sense oligoneucleotides also reduced the surface expression, but not total expression, of cubilin (33). This may indicate that megalin is also involved in trafficking of cubilin.
In addition to direct receptor interaction, megalin and cubilin seem to share ligands. So far, these include RAP and albumin (Table 1). Thus in the case of albumin both megalin and cubilin are involved in the endocytic uptake (Fig. 1) (8, 98). This may include direct binding of albumin to both receptors as well as receptor-receptor interaction after binding to cubilin.Vitamin Metabolism and Homeostasis
The megalin-mediated tubular reabsorption of vitamin-carrier proteins appears important for both maintaining vitamin homeostasis and metabolizing certain vitamins, notably the renal hydroxylation of vitamin D. So far, three vitamin-carrier proteins (Table 1), all of which are filtered in the glomeruli, have been identified as ligands for megalin. These are DBP, RBP, and TC-B12. DBP (71) and RBP (18) were both initially identified in the urine of megalin-deficient mice, and TC, which previously was identified as a ligand for megalin (63), has also subsequently been demonstrated in the urine of these mice (Birn H, Willnow T, Nielsen R, Norden AGW, Moestrup S, Nexo E, and Christensen E, unpublished observations).Filtered plasma vitamin D carrier protein DBP binds to megalin, which mediates the endocytosis of this protein. The megalin-mediated uptake of 25-(OH) vitamin D3 in the proximal tubule is followed by lysosomal degradation of DBP and subsequent conversion of 25-(OH) vitamin D3 to 1,25-(OH)2 vitamin D3, which is then returned to the circulation (71). Considerable amounts of DBP and 25-(OH) vitamin D3 are excreted in the urine of megalin-deficient mice (71). In addition, these mice have reduced plasma vitamin concentration. Furthermore, especially the young mice suffer from severe bone calcification abnormalities, indicating that megalin-mediated tubular uptake is essential for normal calcium homoestasis in these animals (71).
Megalin also mediates the reabsorption of RBP (18) and TC (63) by endocytosis. This must be followed by release of internalized vitamins to the circulation to maintain vitamin homeostasis. Increased amounts of both TC and vitamin B12 can be identified in the urine of megalin-deficient mice in combination with reduced kidney concentrations of B12 (Birn H, Willnow T, Nielsen R, Norden AGW, Moestrup S, Nexo E, and Christensen E, unpublished observations). This shows that megalin is important for preventing urinary loss of the vitamins. In addition, the kidney may serve a vitamin B12 storage function, possibly involving megalin-mediated uptake (Birn H, Willnow T, Nielsen R, Norden AGW, Moestrup S, Nexo E, and Christensen E, unpublished observations). It has been estimated that the tubular vitamin B12 reabsorption is similar to the intestinal uptake (56).
Although the basic molecular mechanisms for the efficient tubular
clearance of the carrier proteins appear well established, the
subsequent intracellular handling of the vitamins remains to be
clarified. After release of vitamins, the carrier proteins most likely
are degraded in lysosomes. The vitamins may be transported into the
cytoplasm by either diffusion through the vesicular membranes or
facilitation by a transport protein. A membrane-associated vitamin
B12 transporter has been described (39, 77).
Vitamin D3 subsequently undergoes hydroxylation to a more
active form, and, similarly, cobalamin may be metabolized into other
forms. The final steps, i.e., the release of vitamin and possible
coupling to plasma carrier proteins, have not been elucidated. Because vitamin D3 is lipophilic, it has been hypothesized that the
vitamin diffuses through the basolateral membranes and meets its
carrier protein DBP extracellularly (71). Alternatively,
it has been suggested that reabsorbed retinol or B12 is
coupled to newly synthesized RBP or TC within the proximal tubule cells
and then secreted as a complex (18, 70). These pathways
are summarized in Fig. 4.
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The importance of megalin for the uptake and transport of certain vitamins may be indicated by the fact that some of the defects seen in the megalin-deficient mice resemble syndromes of vitamin deficiency. Megalin is located in the visceral epithelium of the yolk sac (15, 25), important for early embryonic nutrition in rodents, and in addition is also in the cytotrophoblast of the placenta (58). Thus megalin may be involved in the transport of vitamins from the maternal circulation to the embryo. It has been hypothesized that megalin and possibly other members of the LDL-receptor family serve an important function mediating tissue-specific uptake of carrier-bound retinoids and steroids, including vitamins and hormones (93). This would provide a mechanism by which certain cell types could accumulate large quantities of steroids beyond what is possible solely by diffusion of free hormones.
Calcium
Megalin serves important functions in calcium homeostasis. As described, megalin mediates proximal tubule endocytosis of the DBP-vitamin D complex, resulting in the renal hydroxylation and activation of vitamin D (71). In addition, megalin mediates tubular uptake and subsequent lysosomal degradation of PTH (36). It has been suggested that this may regulate the amount of PTH available for stimulation of the tubular PTH/PTH-related peptide receptor (36). Megalin is also expressed on the PTH-secreting cells in the parathyroid gland (57) and is, in itself, a very strong calcium binder (17). Thus it may be speculated that the protein serves as a calcium sensor in both the parathyroid gland and the kidney.Drugs
Megalin has been shown to bind and mediate proximal tubule uptake of several polybasic and potential nephrotoxic substances, including the aminoglycosides gentamicin, netilimicin, and amikacin, as well as polymyxin B (64). These drugs are readily filtered in the glomeruli followed by endocytic uptake and accumulation in the endocytic apparatus and lysosomes of the proximal tubule cells (68, 69, 89). Binding to phospholipids in the apical brush-border membrane has been implicated in the tubular uptake (82); however, the affinity of these drugs for megalin is higher than for phosphatidylinositol, suggesting that aminoglycosides bound to membrane lipids are transferred to megalin for endocytosis (64). Also, the expression of megalin in the labyrinthic cells of the inner ear is intriguing (62, 97) because aminoglycosides as well as polymyxin B are also known to be ototoxic.Heymann Nehpritis
Megalin was originally identified as the antigen in Heymann nephritis (43), a rat model of human membranous glomerulonephritis (reviewed in Ref. 26). Circulating anti-megalin antibodies bind to megalin expressed in glomerular podocytes, causing destruction of the basement membrane.So far, no anti-megalin antibodies have been associated with any human renal disease. However, circulating anti-megalin antibodies have been identified in serum from patients with autoimmune thyroiditis as well as some other thyroid diseases (59). Whether these antibodies are involved in the pathogenesis of the underlying autoimmune disease remains to be established.
Signaling Functions?
The megalin cytoplasmic domain contains several regions, suggesting a possible signaling function in addition to its role as endocytic receptor. These include several Src homology 3 and one Src homology 2 recognition sites as well as the NPXY motifs. So far, no definite evidence for the involvement of megalin in signal transduction has been published. However, other members of the LDL-receptor family, the VLDL receptor and apo E receptor-2, have been suggested to be involved in signal transmission initiated by the extracellular matrix protein reelin in the cerebral cortex and cerebellum (88; for recent reviews, see Refs. 35 and 93). This signaling requires the intracellular mammalian disabled protein 1 (Dab1), which was shown to bind to the NPXY motifs on the cytoplasmic tail of both receptors. After binding of Dab1 to the cytoplasmic tail of the VLDL-receptor or apo E receptor-2, Dab1 may be phosphorylated on tyrosine residues, allowing binding and activating nontyrosine kinases. Dab1 has been shown to bind to other members of the LDL-receptor family (38). Also, by using a yeast two-hybrid system, it was recently shown that the cytoplasmic tail of megalin binds the cytosolic disabled protein 2 (Dab2) (72) as well as a number of other cytoplasmic proteins with a potential signaling function (30). Although no specific cellular response has been associated with these interactions involving megalin, Dab2 was identified in rat kidney by Western blotting and was coprecipitated with megalin by using both anti-Dab2 and anti-megalin antibodies (72). This indicates a potential signaling pathway involving megalin in the kidney.Thus several lines of evidence indicate that members of the LDL-receptor family may be involved in signal transduction although no specific response or overall pathway has been identified for megalin.
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CONCLUSIONS |
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Megalin and cubilin constitute two large, endocytic receptors heavily expressed in the endocytic apparatus of the kidney proximal tubule. Absence or dysfunction of either receptor is associated with significant tubular proteinuria, showing that both are important for normal absorption of filtered proteins, including albumin. Although structurally very different, both receptors may be functionally linked. Some ligands are common to both receptors, and megalin-cubilin interaction seems to be important for the endocytosis and recycling of the "peripherally attached" cubilin. Megalin is important for tubular uptake and metabolism of several hormones and vitamin-carrier protein complexes, including the renal activation by hydroxylation of vitamin D. In addition, megalin is involved in the tubular uptake of potential nephrotoxic drugs, including aminoglyocosides. Thus modification of receptor function may be a valuable prospect of future research. This is encouraged by findings suggesting that tubular uptake of an increased load of filtered proteins, including albumin, may contribute to the progression of chronic renal disease. Finally, there is new evidence suggesting that megalin may be involved in signal transduction. No doubt, future studies will help to unfold this potential new aspect of megalin receptor function.
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ACKNOWLEDGEMENTS |
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This work was supported by grants from the Danish Medical Research Council, the Novo Nordic Foundation, the Danish Biotechnology Program, and University of Aarhus Research Foundation.
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FOOTNOTES |
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Address for reprint requests and other correspondence: E. I. Christensen, Dept. of Cell Biology, Institute of Anatomy, Univ. of Aarhus, DK-8000 Aarhus C, Denmark (E-mail: eic{at}ana.au.dk).
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