Department of Medicine, Harvard Medical School and Renal Unit, Massachusetts General Hospital, Charlestown, Massachusetts
Address correspondence to: Dr. Iain A. Drummond, Department of Medicine, Harvard Medical School and Renal Unit, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129. Phone: 617-726-5647; Fax: 617-726-5669; E-mail: idrummond{at}partners.org
Unraveling the molecular pathogenesis of human disease presentsmany experimental challenges, not the least of which is thatexperiments on humans are generally frowned upon. Model organisms,including the zebrafish, allow for experimental analysis ofgene function and the detailed characterization of disease processes.Zebrafish have matured as a vertebrate model organism now thatgenetic tools for targeted "knockdowns" and unbiased mutagenesisapproaches are in hand. The fish larval pronephros is a relevantkidney in which to pursue many aspects of human kidney developmentand disease. This short review outlines recent progress in applyingthe zebrafish pronephros to issues of human health and development.
Studies of kidney function in lower vertebrates have had a significantimpact on our understanding of basic kidney physiology. Thefirst demonstration of tubular epithelial secretion was performedby Marshall (1) in the aglomerular kidneys of the goose fishand toadfish. Our current understanding of fluid secretion mechanismswere originally worked out using the shark rectal gland (2).Renal micropuncture experiments that first revealed the compositionof the glomerular filtrate were performed in the frog (3). Smith(4) studied the kidney in many species of fish, taking advantageof their broad range of habitats to explore important aspectsof renal physiology as well as vertebrate evolution. Exploringkidney development and disease in the fish is a natural extensionof these early studies. Studies of kidney development and diseaseaim to uncover the origins of complexity in the kidney and molecularpathogenesis underlying tissue dysfunction (5): How are specializedcells and structures of the kidney derived from undifferentiatedembryonic tissues? Can developmental processes be recapitulatedin the context of organ injury and repair? How can organogenesisin the fish be exploited to learn about human disease? Thisshort review illustrates how genetic analysis of zebrafish pronephricdevelopment is helping to answer these questions.
The maturation of the zebrafish as a model of vertebrate organogenesisowes to (1) its relative simplicity in terms of organ size andcell number, (2) the feasibility of applying both forward andreverse genetic tools to define gene function, and (3) its accessibilityto observation. Zebrafish embryos develop in freshwater outsidethe mother and are transparent; observation and manipulationof organ development are relatively straightforward (6). Developmentoccurs rapidly, with embryos progressing from fertilized eggto free-swimming larvae in 2.5 d; all stages of organ developmentcan be observed in this short time window. Their high fecundity,their relatively short generation time, and the ability to observeinternal organ development have made large-scale, unbiased mutagenesisscreens possible in a vertebrate (7). Hundreds of mutationsthat affect individual organ systems have been isolated, withvarious defects including cardiac arrhythmias (8), gut and hepaticdegeneration (9), failed blood cell development (10), and cysticdisease of the kidney (11). Sequencing the zebrafish genomeis predicted to be complete in 2005 (12), and the existing sequencedata are already useful for finding gene homologs in zebrafishusing bioinformatic methods. Full-length cDNA projects are alsounder way, and microarrays that represent approximately 15,000genes are available for screening. Gene targeting with antisensemorpholino oligos is highly efficient for gene "knockdowns"and is effective for at least the first 50 h of development,well within the time period of organogenesis (13). With thesemethods for defining gene function coupled with the feasibilityfor high-throughput screening of bath-applied small moleculesand drugs for effects on development and disease phenotypes,the zebrafish is a viable system for modeling many human diseasesand offers an in vivo assay system for drug development (14).
Structure and Function of the Zebrafish Pronephros
In zebrafish and other teleosts, the functional larval pronephrosconsists of only two nephrons with glomeruli fused at the embryomidline just ventral to the dorsal aorta (Figure 1) (11,15–17).Although simple in form, the pronephric glomerulus is composedof cell types that are typical of higher vertebrate kidneys,including fenestrated capillary endothelial cells, podocytes,and polarized tubular epithelial cells (Figure 1, B and C) (11).Two pronephric tubules connect the glomerulus to the pronephricducts, which run caudally and fuse just before their contactwith the outside world at the cloaca. The zebrafish pronephricnephrons form a closed system of blood filtration, tubular resorption,and fluid excretion. The primary function of the fish pronephrosis for osmoregulation. Without a functional kidney, larvae dieof gross edema because they have salty blood and yet live ina very dilute environment.
Figure 1. Structure of the functional larval pronephros. (A) Diagram of the mature zebrafish pronephric kidney in 3-d-old larva. A midline compound glomerulus connects to the pronephric tubules that run laterally and drain into the pronephric ducts. The ducts are joined at the cloaca, where they communicate with the exterior. (B) Polarized distribution of the NaK ATPase in 2.5-d-old pronephric duct epithelial cells visualized by the 6F monoclonal antibody. The apical cell surface (Ap) is devoid of staining, whereas staining is strong on the basolateral cell surface and membrane infoldings (Bl). (C) Electron micrograph of 2.5-d-old pronephric duct epithelial cells showing apical (Ap) brush border and basolateral (Bl) cell surfaces and infoldings. (Inset) Enlarged view of the apical cell junction showing a well-developed adherens junction.
The pronephric kidney forms in a stepwise progression that,in general terms, follows the sequence observed in mammaliankidney development (18). First, the pronephric duct, the futurecollecting system, is formed by the conversion of loose fibroblasticcells into a polarized epithelial tube. The nephrons then formand connect to the pronephric duct at its anterior tips, and,finally, blood vessels sprout and invade the podocytes to formthe glomerulus. This process occurs only once in the zebrafishembryo during the first 2 d of development. Thus, all of therelevant cellular interactions and the genes that control kidneydevelopment can be studied over a relatively short period ina simple and accessible kidney.
Defects in Glomerulus Formation and Nephrotic Syndromes
Proper functioning of the kidney requires a structural integrationof glomerular podocytes and blood vessels. In zebrafish, evidencethat podocytes act to organize vessel ingrowth can be seen in(1) the expression patterns of genes that are known to playan important role in angiogenesis and (2) the recruitment ofendothelial cells to clusters of podocytes in mutant embryosthat lack the dorsal aorta, the normal blood supply for thepronephric glomerulus. Zebrafish pronephric podocytes expresstwo known mediators of angiogenesis: Vascular endothelial growthfactor (VEGF) and angiopoietin 2 (19,20). In a complementarymanner, capillary-forming endothelial cells express flk1, aVEGF receptor and an early marker of the endothelial differentiationprogram (21). In normal zebrafish embryos at 40 hpf, flk-1–positiveendothelial cells invade the glomerular epithelium and formthe capillary loop. In floating head mutant embryos, the dorsalaorta is absent (22), and so the nascent glomeruli are deprivedof their normal source of vasculature. Nonetheless, podocytescontinue to express wt1 and vegf and seem to recruit flk-1–positiveendothelial cells from nearby veins and go on to form a reasonablyfunctional glomerulus (19). These results support the idea thatpodocytes, by expressing vegf, play a primary role in attractingand assembling the glomerular capillary tuft.
Surprisingly, zebrafish mutants that lack blood flow as a resultof defects in cardiac function (23) fail to form a proper glomerularcapillary tuft (Figure 2, A and B). This suggests that vascularshear force per se is required to drive capillary formation(24). Although vascular cells seem normal, they fail to expressmatrix metalloproteinase-2. Inhibition of matrix metalloproteinaseactivity by tissue inhibitor of metalloproteinase-1 injectionsresults in a similar failure to form the glomerulus (24), indicatingthat degradation and remodeling of the glomerular basement membraneis a key step in capillary tuft formation.
Figure 2. The zebrafish as a model of glomerular structure and function. (A) An electron micrograph of the forming glomerulus at 2.5 dpf with invading endothelial cells from the dorsal aorta shaded in red and podocytes shaded in blue (image false-colored in Adobe Photoshop). (B) A similar stage glomerulus in the mutant island beat, which lacks blood flow as a result of a mutation in an L-type cardiac-specific calcium channel. The endothelial cells and podocytes are present, but there is no sign of glomerular remodeling and morphogenesis. (C) Measuring renal clearance: Rhodamine-dextran filtration and uptake by pronephric epithelial cells. 10KD lysine-fixable rhodamine dextran injected into the general circulation can be seen as red fluorescence in glomerular capillaries (gl), and filtered dye is seen in apical endosomes of pronephric duct cells (arrowheads). Counterstain: FITC wheat germ agglutinin. (D) Electron micrograph of the glomerular basement membrane (gbm) region in the glomerulus. Individual profiles of podocyte foot processes resting on the glomerular basement membrane (gbm) are connected by slit diaphragms (arrowheads at top). Cl, capillary lumen; bs, Bowman’s space. Whole-mount in situ hybridization shows expression of zebrafish podocin (E) and nephrin (F), genes associated with human nephrotic syndromes, specifically in the forming podocyte precursor cells.
Filtration of blood by the pronephric glomerulus can be detectedby injections of fluorescence compounds into the general circulationand then monitoring the appearance of fluorescent endosomesin the apical cytoplasm of pronephric duct cells (Figure 2C)(11,19). From these data, it can be inferred that the fluorescencetracer has passed the glomerular basement membrane and enteredthe lumen of the pronephric tubules and ducts, where it is activelyendocytosed. Using this assay, we have established that bloodfiltration by the zebrafish pronephros begins at approximately40 hpf (11).
A major feature of the mammalian glomerular blood filter isthe podocyte slit diaphragm, a specialized adherens junctionthat forms between the podocyte foot processes (25). Failureof the slit diaphragm to form results in proteinuria or leakageof high molecular weight proteins into the filtrate. Proteinuriais the cardinal feature of several human congenital nephropathiesand also a common complication of diabetes (26). Several diseasegenes that are known to function in the slit diaphragm havebeen cloned. Nephrin is a transmembrane protein present in theslit diaphragm itself and is thought to contribute to the zipper-likeextracellular structure between foot processes (27). Podocinis a podocyte junction–associated protein (28) that resemblesstomatin proteins, which play a role in regulating mechanosensitiveion channels (29). Electron microscopy of the zebrafish pronephricglomerulus reveals that like mammalian podocytes, zebrafishpodocytes form slit diaphragms between their foot processes(Figure 2D). Zebrafish homologs of podocin and nephrin are specificallyexpressed in podocyte precursor cells as early as 24 hpf (Figure 2, E and F).These functional similarities between mammalianand zebrafish podocytes, coupled with assays for glomerularfiltration, point to future applications of fish as a modelfor study and treatment of human proteinuria.
Defects in Tubules and Models of Cystic Disease
One of the most common human genetic diseases is polycystickidney disease, which affects 1 in 1000 individuals (30). Kidneycysts are the result of grossly expanded kidney tubule lumensand, when present in sufficient size and number, lead to kidneyfibrosis and end-stage renal failure. Our work has identifieda relatively large set of genetic loci associated with cysticpronephroi in zebrafish (11) (Figure 3). Recently, the resultsof a large-scale retroviral insertional mutagenesis screen haveidentified 10 zebrafish genes that when mutated cause pronephriccysts (31). The requirement for a relatively large number ofgenes underlying maintenance of tubule structure is consistentwith the idea that maintenance of lumen size and epithelialcell shape is a complex process that is controlled by many cellularproteins or signaling pathways.
Figure 3. The zebrafish as a model of polycystic kidney disease. Three-day-old larvae showing wild-type (A) and the mutant double bubble (dbb; B) with a grossly distended pronephric tubule that appears as a bubble (arrow) just behind the pectoral fin. (C) Three-day-old wild-type kidney structure showing the pronephric duct (pnd; cross-section), pronephric tubule (pt), and glomerulus (gl). (D) A section of a dbb mutant pronephros shows the cystic distended lumen of the pronephric tubule (*) and distended glomerulus at the midline. (E) Whole-mount confocal immunofluorescent image of a 3-d-old embryo stained with anti-acetylated tubulin to reveal cilia in the pronephric ducts (arrowhead). Dorsal structures are the neural tube and motor neurons. (F) Close-up view of acetylated tubulin–positive pronephric cilia. (G) Electron micrograph of a single apical cilium (arrowhead) on a pronephric duct cell.
A surprising convergence of findings from studies of cysticdisease, left-right asymmetry, retinal degeneration, and flagellaformation in the simple eukaryote Chlamydomonas have led tothe idea that defects in the formation or function of ciliamay underlie the pathology observed in all of these conditions.Cloning the gene that is responsible for the oakridge polycystickidney (orpk) mouse was the first link between cilia and kidneycystic disease. The mutant gene, polaris, is a homolog of aChlamydomonas gene, IFT88, that is required for intraflagellartransport, an essential process in flagellum formation (32,33).Human and mouse kidney cells are not flagellated but have asingle, nonmotile apical cilium. Orpk mutant mouse kidney epithelialcells have short, malformed apical cilia (32–34), suggestinga functional link between cilia and maintenance of epithelialtubule lumen diameter. Subsequent studies revealed that mostknown cystic mutant genes, including polycystin 1, polycystin2, cystin (cpk mouse), polaris, inversin, and the Caenorhabditiselegans polycystin homologs lov-1 and pkd2, were, at least inpart, localized to cilia (35–39). The results of a large-scaleinsertional mutagenesis screen in zebrafish lend further supportto the link between cilia and cystic disease. Of 10 genes reportedin this work, three were IFT genes associated with ciliogenesis(31). Recent studies of polycystin 1 and polycystin 2, the genesthat are responsible for autosomal dominant polycystic kidneydisease, indicate that they act together to mediate calciumentry into cells upon flow-induced cilium deflection (40,41).The current model of cilia function in the mammalian kidneyis that the cilium acts as a sensor of tubule lumen mechanicsand flow, providing a feedback signal that limits lumen diameteror cell proliferation. Our recent observations in zebrafishindicate that cilia in the pronephros are motile and have a"9 + 2" microtubule doublet organization that is typical ofmotile cilia and flagella (Kramer-Zucker et al., submitted).Because motile cilia are often associated with fluid flow, thisleads to an alternative hypothesis that cilia may act as a fluidpump in the zebrafish pronephros. It seems that cystic kidneytubules could arise by multiple different mechanisms relatedto cilia function.
Several other genes that can account for tubule cyst formationhave been identified in zebrafish. Nek8 is a member of the NIMAfamily of serine/threonine kinases and is mutated in the juvenilecystic kidney (jck) mouse (42). Disrupting the function of zebrafishNek8 causes severe cystic distension of the pronephric tubules.Other Nek kinases have links to cytoskeletal functions: Nek2is localized to centrioles and acts to promote splitting ofduplicated centrioles during the cell cycle (43). Further studiesare needed to test whether Nek8 may have a similar role in ciliumor centrosome/basal body function (44–47).
Disruption of the zebrafish homolog of the human cystic diseasegene polycystin 2 also causes pronephric cyst formation (31;Obara et al., unpublished results, 2004). We have found thatco-injected human polycystin 2 mRNA can rescue this phenotype,indicating that the function of polycystin 2 has been highlyconserved between fish and human. This kind of result opensto the door for functional analysis of variant forms of thehuman PKD2 gene in an easily manipulated, in vivo model of humandisease.
Disruption of the zebrafish inversin gene results in kidneycysts. The human condition nephronophthisis type 2 (NPHP2) isassociated with mutations in the human inversin gene (13). Bothinversin and the mammalian NPHP1 gene nephrocystin are foundin basal bodies and cilia and have been shown to interact biochemically.Deletion of the putative nephrocystin-binding domain in zebrafishinversin results in severe cyst formation, supporting the ideathat NPHP proteins act as a multiprotein complex to regulatethe function of basal bodies and/or cilia (13).
The transcription factor hepatocyte nuclear factor 1 (HNF-1)is required for normal zebrafish pronephric tubule development(48) and, when mutated, results in glomerular cysts. HNF-1 hasbeen shown to regulate the expression of several other cyst-associatedgenes in the mouse (49). Mutations in HNF-1 in humans are associatedwith glomerulocystic disease and maturity onset diabetes ofthe young, type V (50).
Despite some differences in organ morphology between the mammalianand teleost kidneys, many parallels exist at the cellular andmolecular levels that can be exploited to further our understandingof kidney development and disease. The same genes and cell typesare used in the development and function of all vertebrate kidneys.Genes that are mutated in human disease are also essential forthe formation and function of the zebrafish pronephros. Thezebrafish thus presents a useful and relevant model for studiesof kidney development and disease. Both gene-targeted and unbiasedmutagenesis approaches to genetic manipulation in the zebrafishwill no doubt continue to reveal the function of genes and cell–cellinteractions that underlie the development of all kidney forms.
Acknowledgments
This work was supported by National Institutes of Health GrantsDK53093 and DK54711 to I.A.D.
I thank present and past members of the laboratory (Tomoko Obara,Albrecht Kramer-Zucker, Stephanie Wiessner, Narendra Pathak,Arindam Majumdar, and Angela Zhao) for contribution to thiswork and collaborators Mark Fishman, Fabrizio Serluca, and DavidBeier for productive interactions.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Top
Abstract
Introduction
(HNF-1
6F monoclonal antibody. The apical cell surface (Ap) is devoid of staining, whereas staining is strong on the basolateral cell surface and membrane infoldings (Bl). (C) Electron micrograph of 2.5-d-old pronephric duct epithelial cells showing apical (Ap) brush border and basolateral (Bl) cell surfaces and infoldings. (Inset) Enlarged view of the apical cell junction showing a well-developed adherens junction.
