Renal Tubule Development in Drosophila: A Closer Look at the Cellular Level
Alain C. Jung*,
Barry Denholm,
Helen Skaer and
Markus Affolter*
* Abteilung Zellbiologie, Biozentrum der Universität Basel, Basel, Switzerland; and Department of Zoology, University of Cambridge, Cambridge, United Kingdom
Address correspondence to: Prof. Markus Affolter, Abteilung Zellbiologie, Biozentrum der Universität Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland. Phone: 00-41-61-267-2072; Fax: 00-41-61-267-2078; E-mail: markus.affolter{at}unibas.ch
The function of excretion in insects is performed by the Malpighiantubules, a functional equivalent of the vertebrate kidney. Malpighiantubules are long, thin tubes connected to the hindgut. Uponthe determination of the Malpighian tubule major cell type earlyin embryogenesis, the tubular architecture is achieved by extensivecell division and cell rearrangements. During the tube elongationprocess, cells exchange their neighbors, allowing the shortand fat Malpighian tubule primordia to grow and become a thintube. Cell rearrangement and intercalation underlie the morphogenesisof other epithelial tissues in Drosophila melanogaster, suchas the embryonic epidermis. Recent work has provided insightsin the cellular and molecular basis of cell intercalation. Theseadvances are reviewed and discussed with regard to what is knownabout Malpighian tubule morphogenesis. Mature Malpighian tubulesare composed of two cell types, each having a specific functionin excretion: The principal cells and the stellate cells. Drosophilaand mammalian kidney development show striking similarities,as the recruitment of the stellate cells to the Malpighian tubules,like the cells of the metanephric mesenchyme, requires thatcells undergo a mesenchymal-to-epithelial transition. The molecularsimilarities between these two cases is reviewed here.
Tubular organs are a particularly important feature of metazoans,because the formation of tubes results in an increased surfacearea for interaction with the environment, allowing efficientgas and fluid exchange and thereby facilitating homeostasis.Several tubular organs have been described in higher organisms,such as the lung, the kidney, the liver, and the pancreas. Tubularstructures are also found in insects and include the salivaryglands, the tracheal system, and the Malpighian tubules, a functionalequivalent of the mammalian kidney. Tubulogenesis of these organsoccurs during embryonic development and requires the integrationand coordination of various cellular events such as cell division,cell migration, cell intercalation, and cell shape changes.These processes allow the budding and growth of tubes from amonolayered epithelium, ultimately leading to a functional,often heavily branched epithelial network (for review, see references1–3). Given the high degree of complexity of the regulatorymechanisms that control tubulogenesis in mammals and takinginto account the conservation of regulatory pathways in higherand lower animals, it is expected that studies in simpler andgenetically more tractable model systems, such as Drosophilamelanogaster and Caenorhabditis elegans, will contribute toour understanding of the molecular and cellular details of tubulogenesis.In this review, we first provide a general description of thedevelopment of the Malpighian tubules during Drosophila embryogenesisand highlight a number of striking cellular and molecular parallelsbetween this model system and the development of the vertebratekidney. We then discuss some recent data on the genetic controlof cell rearrangement during epithelial remodeling in the Drosophilaepidermis and assess how emerging ideas from study of this systemare relevant to Malpighian tubule development. Some of the paradigmsdiscussed in the context of the Malpighian tubules might alsoapply to the mammalian kidney. This might help to design novelexperimental approaches and ultimately lead to a better understandingof kidney development.
An Example of Tubulogenesis: Development of the Malpighian Tubules in Drosophila
The Malpighian tubules of the Drosophila larva consist of twopairs of epithelial tubes (Figure 1H) that bud from the hindgutduring embryogenesis (Figure 1, A and B). These buds grow ina stereotyped manner, the longer ones in the direction of thehead of the embryo, the shorter ones toward the posterior end(Figure 1, C through E). At the onset of the budding, the Malpighiantubule primordia consist of six to 10 cells wrapped around theprimitive lumen (Figure 2, B through D). By the end of embryogenesis,the Malpighian tubules have developed into long, thin tubes,with two cells encircling the lumen (Figure 2F) (3). Four differentsteps underlying these dramatic morphogenetic events can bedistinguished: Allocation of the Malpighian tubule primordia,tube budding, tube growth and elongation, and, ultimately, celldifferentiation (for excellent and comprehensive reviews, aswell as for more specific references, see references 3,4).
Figure 1. Embryonic development and anatomy of the Drosophila melanogaster Malpighian tubules. (A through E) Drosophila embryos stained with an antibody raised against the transcription factor Cut, which labels tubule cells throughout development. (A) The tubules evert from the hindgut early in embryogenesis. (B through D) The tubules grow first by cell division (B and C) and later by elongation through cell intercalation and rearrangements (D). (E) Later, the tubules have adopted their stereotyped arrangement within the embryonic cavity. (F) By the end of embryogenesis, the first signs of physiologic activity can be seen as uric acid is deposited into the tubules lumen (revealed as a bright deposit under polarized light). Embryos are shown in lateral view (A) and in dorsal view (B through F), with anterior at left and posterior at right. Black arrowhead, anterior tubule; white arrowhead, posterior tubule. (G) The tubule from a Drosophila larva stained with antibodies raised against the transcription factor Teashirt (Tsh; red) and F-actin (green) and stained for DNA (blue). Stellate cells (SC) are interspersed with principal cells (PC). SC originate from a different cell lineage than PC and express Tsh. Both cell types adopt apicobasal polarity, as demonstrated by the accumulation of F-actin in the microvilli on the luminal side of the cells. (H) Schematic representation of the larval Malpighian tubules in Drosophila. Drosophila has four tubules, a longer anterior and a shorter posterior pair (one tubule of each pair is depicted). They originate at the midgut-hindgut boundary. Each tubule can be divided into four distinct morphologic regions, based on proximodistal differences in cell structure: initial, transitional, and main segments and the ureters.
Figure 2. Schematic representation of the different events underlying Malpighian tubule development. (A) Allocation of Malpighian tubule cells. Early in embryogenesis, interaction between the midgut (red) and the hindgut (blue) anlagen, through signal(s) of unknown identity, refines the domain of expression of the Krüppel (Kr) transcription factor in the hindgut (green) to the future Malpighian tubule PC. Kr is involved in maintaining the expression of the Cut transcription factor. The wingless pathway is thought to play a permissive role in Malpighian tubule cell allocation in parallel to Kr and Cut. (B) Eversion of Malpighian tubules. As a consequence of Kr and Cut expression, Malpighian tubule cells change shape and the tubule primordia evert from the hindgut. The morphogenetic programs triggered by Kr and Cut are not known. (C) Determination of the tip cell. Within the tubule primordia, a new cell lineage is produced (dark blue). A cell called the tip cell (yellow) is singled from this group of competence cells via the Notch pathway. (D) Tubule growth by cell division. Once the tip cell has differentiated, it secretes epidermal growth factor (EGF) and stimulates mitosis in neighboring cells, at the distal end of the tubule. As a consequence, tubules grow by addition of new cells. At this stage of development, the tubule is short and fat, with six to ten cells encircling the lumen. The tubule comes in vicinity to the caudal mesoderm (orange). (E) Tubule growth by cell intercalation. Malpighian tubule cells stop dividing, and tubule growth proceeds through extensive cell rearrangements and intercalation. Subsequently, the diameter of the lumen starts to decrease. During this phase, a subpopulation of caudal mesoderm cells interacts with the tubule; individual cells undergo a mesenchymal-to-epithelial transition (MTE) and progressively incorporate into the tubule epithelium as SC. (F) Functional Malpighian tubules. By the end of embryogenesis, Malpighian tubules have achieved their final architecture. They have undergone a dramatic increase in length and have become very thin, with just two cells around the lumen. They are then functional: PC transport K+ into the lumen, and SC, interspersed with PC, allow the consequent movement of Cl– and water.
Allocation of Malpighian Tubule Cells and Formation of Everted Primordia
Malpighian tubules originate from the hindgut, which itselfresults from an invagination of the posterior ectoderm (Figure 1A).An interaction between the midgut and the hindgut is akey step in the allocation of the major Malpighian tubule celltype, the principal cells. An unknown signal from the midgutspecifies Malpighian tubule fate by refining the expressionof the zinc-finger transcription factor Krüppel (Kr) tothe future Malpighian tubule cells. Kr in turn helps to maintainthe expression of the homeodomain-containing protein Cut inthe same domain (Figure 2A). In addition to this putative inductivesignal(s) emanating from the midgut, signaling through the Wntpathway is required at this early stage for the normal specificationof tubule cells. wingless (wg) is expressed in the inner-mostregion of the proctodeum, where tubule cells arise (5), suggestingthat wg pathway activity could be a permissive signal for tubulecell allocation (Skaer et al., in preparation). As a consequenceof the presence of the Kr and Cut transcriptional regulators,Malpighian tubule cells undergo complex cell shape changes,and tubules start to evert from the hindgut (Figures 1B and2B). In Kr and cut mutant embryos, tubules do not bud, and thecells either remain in the hindgut or form multilayered blisterson the surface of the hindgut, respectively (6–9). However,Kr and Cut are not solely required for Malpighian tubule cellfate determination, as cells with Malpighian tubule–likecharacteristics (e.g., expression of tubule-specific markersin the Malpighian tubules primordia, or accumulation of uricacid, the nitrogenous waste, in the lumen) can still be foundin the hindgut in embryos mutant for either locus. The genesregulated by Kr and Cut, which drive morphologic rearrangementsthat lead to tube eversion, are not yet known, and their isolationrepresents a major goal in the field. These target genes arelikely to encode molecules that regulate the cytoskeleton, modulatecell junctions and adhesion, and direct cell movement and cellshape changes. Strikingly, the mammalian transcription factorsGlis2 and Klf-6, belonging to the Krüppel-family, as wellas Cux-1, the mammalian ortholog of Cut, have been shown toplay a role in kidney development (for review, see reference10 and references therein). However, their speculated role inearly as well as late kidney specification and maturation isnot yet understood.
It is remarkable to note that both in mammals and in Drosophila,the Wnt signaling pathway plays an inductive role in kidneydevelopment. Indeed, knockout mice lacking a functional copyof the Wnt4 gene develop small, dysgenic kidneys, in which apoorly differentiated metanephric mesenchyme is interspersedwith uteric branches (11) (for reviews, see references 12,13).Similarly, the DWnt pathway, in addition to its role in tubulespecification, seems to play a crucial role in determining Malpighiantubule cell number (3,4).
Tubule Morphogenesis
While the tubules are budding, one cell at the tip of the branchesis singled out of a competence group by lateral inhibition throughthe Notch pathway (Figure 2C) (14,15). This tip cell secretesepidermal growth factor (EGF) and promotes cell division byactivating the EGF receptor pathway in its neighbors (Figure 2D),thereby inducing tubule growth by increasing the cell number.Cell division ceases by mid-embryogenesis, and at this stage,the tubules begin to undergo a dramatic phase of elongation,brought about by cell intercalation (Figure 2E). During thisperiod, the tubules increase considerably in length (Figure 1,C through E), and the number of cells surrounding the lumendrops from six to ten to just two (Figure 2F) (3).
Several genes implicated in these concerted and organized cellrearrangements have been identified. Not surprisingly, the Drosophilahomologue of the nonmuscle Myosin II heavy chain, encoded bythe zipper locus, plays a role in the Malpighian tubule cellshape changes and rearrangements that underlie tube elongation(16,17). A similar role in regulating cell shape changes hasbeen proposed for the ribbon gene, which encodes a BTB/POZ domainprotein, perhaps through its ability to regulate the transcriptionof genes encoding components or modulators of the actin cytoskeleton(16,18,19). Yet the precise role of these genes in tubule elongationis not understood at the moment (3), and the molecular processesby which it is orchestrated remain mysterious. However, importantadvances have been made recently in the understanding of cellrearrangement in the epidermis in Drosophila during gastrulation,and we briefly discuss these studies and their possible relevancefor Malpighian tubule development in the last section.
Cell Differentiation
Once the Malpighian tubule cells exit the proliferation program,they grow by regulated endoreplication. Patterned cell differentiationresults in the onset of the physiologic function of the tubulesby the end of embryogenesis, which can be monitored by the appearanceof uric acid in the lumen (Figure 1F). This excretion functionof the Malpighian tubules relies on the presence of two differentcategories of cells: Approximately 484 principal Malpighiantubule cells (PC) interspersed with approximately 110 stellatecells (SC; Figures 1G and 2F) (20). Primary urine productionrelies on the combined activity of the PC, which secrete K+into the lumen by a vacuolar-H+-ATPase transporter and K+/H+exchanger (21,22), and the SC, which express channels to permitthe consequent flow of chloride ions and water (23,24). In insects,the activity of these transporters is hormonally regulated bydiuretic peptides (for review, see reference 25). Again, verylittle is known about the genetic control of cell differentiation,and future experimental efforts have to be launched to closethe link between the establishment of the primordium and thefinal differentiation and function of the cells that make upthe Malpighian tubules.
Dual Cellular Origin of the Drosophila Malpighian Tubules
It was long thought that all of the cells that make up the Malpighiantubules derive from the ectodermal invagination that also givesraise to the hindgut. However, Denholm et al. (20) recentlyshowed that PC and SC derive from distinct cell lineages. Byinjecting genetically labeled nuclei into early embryos, theyobserved that these nuclei were incorporated in 91% of the caseseither in the PC or in the SC and only rarely in both cell types.These results argued in favor of a distinct origin for the SCand their recruitment to the Malpighian tubules. Using a techniqueto mark indelibly cells that express a particular gene, it wasshown that SC come from a cell population that expressed twist,a gene predominantly expressed in the mesoderm, suggesting thatthe SC have a mesodermal origin. Further experiments using thesame technique mapped the origin of SC to a population of mesodermcalled the caudal mesoderm (a subset of the embryonic mesoderm,in the posterior region), which overlies the hindgut exactlyat the location where Malpighian tubules bud from the hindgut.The caudal mesoderm cells express markers, such as the transcriptionfactor Teashirt (see Figure 1G), which are maintained in theSC as they get associated to the developing tubule and incorporateinto the Malpighian tubule epithelium. These markers are neverexpressed in PC.
Despite their mesodermal origin (20), SC adopt epithelial characteristicsonce they have incorporated into the tubules and develop anapicobasal polarity, evident by the expression of specific apicalmembrane markers and by the development of polarized cell architecture(microvilli on the luminal surface [3] and a polarized actincytoskeleton). Thus, Denholm et al. proposed that while theprospective SC are recruited from the caudal mesoderm into thegrowing Malpighian tubules, they undergo a mesenchymal-to-epithelialtransition.
Here, a very striking parallel can be drawn with the developmentof the vertebrate kidney. Indeed, the formation of the vertebratekidney relies on the continuous interaction between the utericbud, which branches from the Wolfian duct and will later giverise to the urine collecting system (collecting ducts and ureters),and the metanephric mesenchyme, which will form the glomeruliand the nephrons (for review, see reference 12). In this caseas well, cells of the metanephric mesenchyme undergo a mesenchymal-to-epithelialtransition, aggregate around the uteric bud and adopt epithelialfeatures.
It is interesting that Denholm et al. provided genetic evidencein favor of additional conservation of similar mechanisms forthe development and function of the kidney in mammals and Drosophila.Nephrins are proteins that belong to the Ig super family ofcell surface molecules. The vertebrate Nephrin is expressedin the slit diaphragm, a key component of the filtration systemof the glomeruli (26). Patients who carry a defective nephringene lack the slit diaphragm and experience a life-threateningcongenital nephrotic syndrome characterized by massive proteinuria(27). Drosophila embryos mutant for the hibris locus, whichencodes the ortholog of vertebrate Nephrin, show a significantlyreduced number of SC, and, as a consequence, the relative rateof fluid secretion of Malpighian tubules is decreased in thismutant (20). The precise role of Hibris in SC development isnot yet understood. However, one possibility is that Hibrisinteracts with other Nephrin-like molecules, which might beexpressed at the surface of the PC and help to stabilize theinteraction of the SC and the Malpighian tubule epithelium.
In both cases, the absence of a functional copy of the Nephringene results in a failure of the proper development and physiologicfunction of the organ. Although the Malpighian tubules and vertebratekidney are very different in both structure and physiology,these results reveal exciting cellular and molecular similarities.These data suggest that knowledge derived from simple modelsystems, such as the Drosophila Malpighian tubules, will provideuseful clues concerning the role of the cellular factors involvedin the development of more complex organs and ultimately leadto a better understanding of the disease.
Cell Intercalation and Cell Rearrangements in Drosophila
One essential and fascinating aspect of tubulogenesis, commonto most tubular organs, is the restructuring of tube architectureby cell rearrangement and cell intercalation during elongation,a process in which cells dynamically exchange their neighbors.As mentioned previously, Malpighian tubules adopt their finalthin morphology through cell intercalation, starting from ashort, fat tube and ultimately forming a long, thin tube inwhich two cells encircle the lumen. However, this process ispoorly characterized in the context of the Malpighian tubules,and the precise role of the few molecular components that areknown to be involved in the process is not well understood.
Does cell intercalation in tubular structures, such as the Malpighiantubules, occur in a manner similar to cell intercalation inother tissues? A recent study has provided novel and excitinginsight into both cellular and molecular aspects of cell rearrangements.In the following section, we describe the results of this studyand discuss them in the light of Malpighian tube development.We expect that these novel results will have an impact on theexperimental strategies used in studying Malpighian tubule developmentand will allow for a better understanding of the processes involvedin its morphogenesis.
Convergent Extension of Drosophila Epidermal Cells during Germ Band Extension
Several distinct tissue movements occur during gastrulationin insects. One of these, germ band extension (GBE), is a developmentalelongation of the embryonic ectoderm along the anterior/posterior(A/P) axis, which results in a nearly twofold elongation ofthe epithelial layer that forms the thorax and the abdomen ofthe Drosophila embryo (Figure 3A). This extension is achievedthrough a convergence movement of epithelial cells, along theembryonic dorsoventral (D/V) axis, from lateral positions towardthe ventral midline region of the embryo (Figure 3B). Remarkably,neither cell division nor cell shape changes are responsiblefor this event; GBE relies solely on cell intercalation.
Figure 3. Myosin II-dependent junction remodeling controls polarized cell intercalation of epidermal cells during germ band extension in Drosophila embryos. All panels are shown with anterior to left and dorsal to the top. (A) Schematic representation of a Drosophila embryo at the onset (a) and completion (b) of germ band extension (GBE). The extending germ band is located ventrally and is represented in dark brown. Because of extensive epidermal cell intercalation, the tissue elongates nearly twofold and extends toward the posterior pole of the embryo (arrows in a and b). Insets show intercalation of cells, as outlined in B. (B) Intercalating epidermal cells during GBE. GBE is achieved through a convergence movement of epithelial cells, along the embryonic dorsoventral (D/V) axis, from lateral positions toward the ventral midline region of the embryo. During this process, tetrads of hexagonal cells (marked with a red dot) change over time from a type 1 configuration of adherens junctions (AJ; red) to a type 2 and finally a type 3 configuration. Type 1: cells along the anterior-posterior (A/P) axis are in contact with each other; cells along the D/V axis are not. Type 2: all cells show equal contact. Type 3: cells along the A/P axis are no longer in contact; cells along the D/V axis are now in contact. The progressive transition from a type 1 to a type 3 configuration results in a dramatic increase of the length of the tissue along the A/P axis. (C) Model for planar epithelial intercalation. Myosin II (yellow) is enriched at the level of AJ running along the D/V axis (type 1) and provides the cells with an intrinsic contractile network that forces polarized AJ remodeling. This tension causes shrinking of the type 1 AJ probably by orienting the disassembly of E-cadherin-based junctions (green). Myosin II is absent from the AJ in type 2 and type 3 configuration. Therefore, it is thought that it provides the energy input for the transition of type 1 to type 2 configuration.
To visualize cellular events during GBE in live embryos, Bertetet al. (28) marked the epithelial adherens junctions (AJ) usinga chimeric Drosophila E-cadherin protein fused to the greenfluorescence protein (GFP). Their analysis revealed that duringGBE, tetrads of hexagonal cells go from a so-called type 1 junctionconfiguration (adjacent cells along the A/P axis are in contactwith each other; cells in the D/V axis are not) to a type 3junction configuration (cells in the A/P axis are no longerin contact; cells along the D/V axis are; Figure 3, B and C).This process goes through an intermediate type 2 junction configuration,where all cells of the tetrads show equal contact. Therefore,it seems that the extension of the epithelium along the A/Paxis is not due to a concerted cell movement but rather to ahighly organized remodeling of the AJ that results in the polarizedrearrangements of cell neighbors within the plane of the epithelium.This is driven by a sequential change in the configuration ofAJ over time (from the type 1 to the type 2 and to the type3).
GBE is incomplete in mutant embryos that lack the function ofthe Kr transcription factor. Bertet and collaborators showedthat although the three types of junction are present in thismutant background, the sequence of their transition is no longerobserved. The distribution between type 1, type 2, and type3 seems to be more random, and "backward" transitions are sometimesobserved. In Kr mutants, GBE is incomplete as a result of reductionin organized junction remodeling over time.
Where does the force, which leads to the concerted transitionof type 1 into type 3 junctions, come from? It seems that Kris required for the asymmetric recruitment of the Myosin IIheavy chain (encoded by the zipper [zip] gene) and the MyosinII regulatory light chain (encoded by the spaghetti squash [sqh]gene), which are enriched along the shrinking type 1 junctions(Figure 3C). In embryos that lack the function of either zipor sqh, epithelial cell intercalation is severely disrupted.The formation of an active Zip/Sqh complex requires phosphorylationof Sqh by Rho-kinase (Rok). Injection of an inhibitor of Rokreduces the recruitment of Sqh to the type 1 AJ and affectsGBE in a dose-dependent manner. On the basis of these data,the authors propose that the polarized recruitment of MyosinII contractile activity at the level of type 1 AJ creates alocal tension that orients the disassembly of junctional E-cadherincomplexes (Figure 3C). As a consequence, the polarized intercalationof the cell within the plane of the epithelium leads to theelongation of the tissue (Figure 3B).
As mentioned above, a role in Malpighian tubule cell shape changesand tubule elongation has been proposed for Zip, yet the preciseaction of Zip in this context has not yet been elucidated. Doesit act together with Sqh? Does Zip influence the remodelingof AJ in Malpighian tubules? Where does Zip localize in thecells during rearrangement? Those questions should now be addressed,and the results obtained might shed light on how epithelialtubes are remodeled during development.
Whereas GBE is controlled by internal forces, the elongationof the branches in the another insect tubular organ, the developingtracheal system, has been proposed to be under the control ofexternal pulling forces exerted by actively migrating tip cells(see reference 29). It is not clear whether cell rearrangementsin the growing Malpighian tubules are the consequence of internaland/or external forces. During tubule elongation, the tip cellsof the anterior and posterior tip cells establish specific contactswith neighboring tissues. The possible tension in the tubuleresulting from the anchoring of the tip cells might serve asan external force and aid cell rearrangements. However, whenthe tip cells are experimentally removed, Malpighian tubules,although in disarray, reach the stage in which only two cellsencircle the lumen (4,15; unpublished data), demonstrating thatcell intercalation is not affected to any great degree; thus,tip cell anchoring and the tension that this might provide donot seem to be absolutely required for tubule cell rearrangement.Recent data suggest that the small Rho guanosine triphosphatases(GTPase) Rho and Rac could be involved in tubule elongation(Skaer et al., unpublished). These GTPases are known to be regulatorsof cytoskeleton organization. These results, together with theimplication of the myosin II heavy chain Zip in cell intercalation,argue in favor of an intrinsic force to rearrange the Malpighiantubule cells. Live imaging and protein localization studiescan now be combined with genetic studies in Malpighian tubuledevelopment, and this should eventually provide a much clearermolecular picture of tubule growth. Because very little is knownabout tube growth and elongation in mammalian tissues, thesestudies might elucidate tubulogenesis in more complex organs.
The mammalian kidney and Drosophila Malpighian tubules havedifferent general organization and physiology. However, theembryonic development of these organs uses common strategies,such as the interaction of two distinct cell populations, oneof which undergoes mesenchymal-to-epithelial transition. Somepathways or molecules involved in the induction of tubulogenesis(Dwnt) or cell differentiation (Nephrin) seem to have been conservedthrough evolution. Novel tools, including live imaging, haverecently opened the door to new fields of investigation andhave made possible the study, in vivo, of dynamic processessuch as cell intercalation during the morphogenesis of tubularorgans (29). Direct observation of cell movements within a developingepithelium will lead to a more complete picture of how cellsrearrange and provide a fuller understanding of the molecularcomponents involved. It can be expected that future studiesin Drosophila will strengthen our knowledge about the developmentof the mammalian kidney.
Acknowledgments
Work on the Drosophila Malpighian tubules in the laboratoryof H.S. is supported by the Wellcome Trust and BBSRC. Work inthe laboratory of M.A. is supported by the Swiss National ScienceFoundation and the Kantons Basel-Stadt and Basel-Land.
We thank Clemens Cabernard and Marc Neuman for critical comments.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Abstract
Introduction
