The zebrafish pronephros: A model to study nephron segmentation
2008; Elsevier BV; Volume: 73; Issue: 10 Linguagem: Inglês
10.1038/ki.2008.37
ISSN1523-1755
AutoresRebecca A. Wingert, Alan J. Davidson,
Tópico(s)Birth, Development, and Health
ResumoNephrons possess a segmental organization where each segment is specialized for the secretion and reabsorption of particular solutes. The developmental control of nephron segment patterning remains one of the enigmas within the field of renal biology. Achieving an understanding of the mechanisms that direct nephron segmentation has the potential to shed light on the causes of kidney birth defects and renal diseases in humans. Researchers studying embryonic kidney development in zebrafish and Xenopus have recently demonstrated that the pronephric nephrons in these vertebrates are segmented in a similar fashion as their mammalian counterparts. Further, it has been shown that retinoic acid signaling establishes proximodistal segment identities in the zebrafish pronephros by modulating the expression of renal transcription factors and components of signaling pathways that are known to direct segment fates during mammalian nephrogenesis. These findings present the zebrafish model as an excellent genetic system in which to interrogate the conserved developmental pathways that control nephron segmentation in both lower vertebrates and mammals. Nephrons possess a segmental organization where each segment is specialized for the secretion and reabsorption of particular solutes. The developmental control of nephron segment patterning remains one of the enigmas within the field of renal biology. Achieving an understanding of the mechanisms that direct nephron segmentation has the potential to shed light on the causes of kidney birth defects and renal diseases in humans. Researchers studying embryonic kidney development in zebrafish and Xenopus have recently demonstrated that the pronephric nephrons in these vertebrates are segmented in a similar fashion as their mammalian counterparts. Further, it has been shown that retinoic acid signaling establishes proximodistal segment identities in the zebrafish pronephros by modulating the expression of renal transcription factors and components of signaling pathways that are known to direct segment fates during mammalian nephrogenesis. These findings present the zebrafish model as an excellent genetic system in which to interrogate the conserved developmental pathways that control nephron segmentation in both lower vertebrates and mammals. The kidney functions to remove nitrogenous waste from the body as well as to regulate fluid balance, osmolarity, and pH. To accomplish these varied tasks, the individual nephrons are comprised of specialized segments that perform a unique combination of solute transport functions.1.Hebert S.C. Reilly R.F. Kriz W. Structural–functional relationships in the kidney.in: Schrier R.W. Diseases of the Kidney and Urinary Tract. 7th edn. Lippincott Williams and Wilkens, Philadelphia2001: 3-57Google Scholar, 2.Reilly R.F. Ellison D.H. Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy.Physiol Rev. 2000; 80: 277-313Crossref PubMed Scopus (279) Google Scholar, 3.Jacobson H.R. Functional segmentation of the mammalian nephron.Am J Physiol. 1981; 241: F203-F218PubMed Google Scholar Until recently, there has been only a poor understanding of the developmental mechanisms that govern how nephrons are patterned into discrete segments.4.Dressler G.R. The cellular basis of kidney development.Annu Rev Cell Dev Biol. 2006; 22: 509-529Crossref PubMed Scopus (445) Google Scholar, 5.Kopan R. Cheng H.T. Surendran K. Molecular insights into segmentation along the proximal–distal axis of the nephron.J Am Soc Nephrol. 2007; 18: 2014-2020Crossref PubMed Scopus (56) Google Scholar New studies in zebrafish, as well as frogs, have discovered that the nephrons of the embryonic (pronephric) kidneys have a segmental organization similar to that found in adult (metanephric) mammalian kidneys, thus uncovering conservation between nephrons from different kidney types.6.Anzenberger U. Bit-Avragim N. Rohr S. et al.Elucidation of megalin/LRP2-dependent endocytic transport processes in the larval zebrafish pronephros.J Cell Sci. 2006; 119: 2127-2137Crossref PubMed Scopus (51) Google Scholar, 7.McCarthy R.A. Barth J.L. Chintalapudi M.R. et al.Megalin functions as an endocytic sonic hedgehog receptor.J Biol Chem. 2002; 277: 25660-25667Crossref PubMed Scopus (146) Google Scholar, 8.Nichane M. Van Campenhout C. Pendeville H. et al.The Na+/PO4 cotransporter slc20a1 gene labels distinct restricted subdomains of the developing pronephros in Xenopus and zebrafish embryos.Gene Expr Patterns. 2006; 6: 667-672Crossref PubMed Scopus (25) Google Scholar, 9.Van Campenhout C. Nichane M. Antoniou A. et al.Evi1 is specifically expressed in the distal tubule and duct of the Xenopus pronephros and plays a role in its formation.Dev Biol. 2006; 294: 203-219Crossref PubMed Scopus (33) Google Scholar, 10.Wingert R.A. Selleck R. Yu J. et al.The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros.PLoS Genet. 2007; 3: e189Crossref Scopus (212) Google Scholar, 11.Cartry J. Nichane M. Ribes V. et al.Retinoic acid signaling is required for specification of pronephric cell fate.Dev Biol. 2006; 299: 35-51Crossref PubMed Scopus (60) Google Scholar, 12.Eid S.R. Terrettaz A. Nagata K. et al.Embryonic expression of Xenopus SGLT-1 L, a novel member of the solute carrier family 5 (SLC5), is confined to tubules of the pronephric kidney.Int J Dev Biol. 2002; 46: 177-184PubMed Google Scholar, 13.Mobjerg N. Larsen E.H. Jespersen A. Morphology of the kidney in larvae of Bufo viridis (Amphibia, Anura, Bufonidae).J Morphol. 2000; 245: 177-195Crossref PubMed Scopus (39) Google Scholar, 14.Reggiani L. Raciti D. Airik R. et al.The prepattern transcription factor Irx3 directs nephron segment identity.Genes Dev. 2007; 21: 2358-2370Crossref PubMed Scopus (77) Google Scholar, 15.Tran U. Pickney M. Özpolat B.D. et al.Xenopus Bicaudal-C is required for the differentiation of the amphibian pronephros.Dev Biol. 2007; 307: 152-164Crossref PubMed Scopus (53) Google Scholar, 16.Vize P.D. The chloride conductance channel ClC-K is a specific marker for the Xenopus pronephric distal tubule and duct.Gene Expr Patterns. 2003; 3: 347-350Crossref PubMed Scopus (23) Google Scholar, 17.Zhou X. Vize P.D. Proximo-distal specialization of epithelial transport processes within the Xenopus pronephric kidney tubules.Dev Biol. 2004; 271: 322-338Crossref PubMed Scopus (86) Google Scholar, 18.Zhou X. Vize P.D. Amino acid cotransporter SLC3A2 is selectively expressed in the early proximal segment of Xenopus pronephric kidney nephrons.Gene Expr Patterns. 2005; 5: 774-777Crossref PubMed Scopus (4) Google Scholar These findings raise the exciting prospect of utilizing the benefits of lower vertebrate models to dissect the developmental pathways controlling nephron segmentation. This review will focus on the segment pattern of the zebrafish pronephros, how it compares to frogs and mammals, and how segmental identity is established during zebrafish nephron development. During vertebrate development, a series of three kidney structures arises sequentially from the intermediate mesoderm (IM): the pronephros, the mesonephros, and the metanephros.4.Dressler G.R. The cellular basis of kidney development.Annu Rev Cell Dev Biol. 2006; 22: 509-529Crossref PubMed Scopus (445) Google Scholar Each kidney is made up of nephrons that share a fundamental composition of three parts: a glomerulus for blood filtration, a tubule that reabsorbs and secretes solutes, and a collecting duct (CD) that transports the modified filtrate to a waste disposal site. In mammals and other amniotes, the pronephros and mesonephros exist as transient structures, and they are induced following the formation and posterior migration of the nephric duct.4.Dressler G.R. The cellular basis of kidney development.Annu Rev Cell Dev Biol. 2006; 22: 509-529Crossref PubMed Scopus (445) Google Scholar A series of nephrons are derived from mesenchymal cells located next to the duct, with the anterior-most nephrons referred to as pronephros and the more posterior nephrons making up the mesonephros.4.Dressler G.R. The cellular basis of kidney development.Annu Rev Cell Dev Biol. 2006; 22: 509-529Crossref PubMed Scopus (445) Google Scholar Whereas the pronephros is a vestigial organ, the mesonephros functions during fetal life; however, both of these structures will later degenerate or, in the case of males, become part of the reproductive system.4.Dressler G.R. The cellular basis of kidney development.Annu Rev Cell Dev Biol. 2006; 22: 509-529Crossref PubMed Scopus (445) Google Scholar Meanwhile, the metanephros forms at the caudal end of the nephric duct from an outgrowth, known as the ureteric bud, which interacts with the adjacent mesenchyme and undergoes an elaborate process of branching morphogenesis.4.Dressler G.R. The cellular basis of kidney development.Annu Rev Cell Dev Biol. 2006; 22: 509-529Crossref PubMed Scopus (445) Google Scholar Ureteric bud branching generates an arborized network of CDs. Within the mesenchyme, aggregations of some cells undergo an epithelial conversion to form circular renal vesicles that develop into nephrons, and the remaining mesenchymal cells constitute a stromal population that plays essential signaling roles in regulating ureteric bud branching. Subsequent proliferation and elongation of the renal vesicle creates an ‘S’-shaped tubular body that will be patterned along its proximodistal axis to generate the podocytes that contribute to the glomerulus, followed by a tubular epithelium made up of multiple specialized segments. These segments include the neck, proximal convoluted and straight tubules (PCT and PST), descending and ascending thin limb segments of the loop of Henle (also known as the intermediate tubule), distal straight (or thick ascending limb), distal convoluted tubule, and the connecting tubule, which joins to a CD1.Hebert S.C. Reilly R.F. Kriz W. Structural–functional relationships in the kidney.in: Schrier R.W. Diseases of the Kidney and Urinary Tract. 7th edn. Lippincott Williams and Wilkens, Philadelphia2001: 3-57Google Scholar, 2.Reilly R.F. Ellison D.H. Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy.Physiol Rev. 2000; 80: 277-313Crossref PubMed Scopus (279) Google Scholar, 3.Jacobson H.R. Functional segmentation of the mammalian nephron.Am J Physiol. 1981; 241: F203-F218PubMed Google Scholar (Figure 1a). The epithelial cell populations that make up each tubule segment possess a distinctive ultrastructure and gene expression signature and perform discrete roles in modifying the glomerular filtrate.1.Hebert S.C. Reilly R.F. Kriz W. Structural–functional relationships in the kidney.in: Schrier R.W. Diseases of the Kidney and Urinary Tract. 7th edn. Lippincott Williams and Wilkens, Philadelphia2001: 3-57Google Scholar, 2.Reilly R.F. Ellison D.H. Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy.Physiol Rev. 2000; 80: 277-313Crossref PubMed Scopus (279) Google Scholar, 3.Jacobson H.R. Functional segmentation of the mammalian nephron.Am J Physiol. 1981; 241: F203-F218PubMed Google Scholar Metanephros development thus produces an intricate kidney structure that will contain on the order of a million nephrons and serves as the functioning adult kidney. In lower vertebrates, such as fish and amphibians, the pronephric kidney is functional and comprises a pair of bilateral nephrons that work throughout embryonic and larval (juvenile) stages.19.Drummond I.A. Making a zebrafish kidney: a tale of two tubes.Trends Cell Biol. 2003; 13: 357-365Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 20.Jones E.A. Xenopus A prince among models for pronephric kidney development.J Am Soc Nephrol. 2005; 16: 313-321Crossref PubMed Scopus (49) Google Scholar, 21.Reimschuessel R. A fish model of renal regeneration and development.ILAR J. 2001; 42: 285-291Crossref PubMed Scopus (117) Google Scholar, 22.Vize P.D. Seufert D.W. Carroll T.J. et al.Model systems for the study of kidney development: use of the pronephros in the analysis of organ induction and patterning.Dev Biol. 1997; 188: 189-204Crossref PubMed Scopus (166) Google Scholar A mesonephros develops later, during larval life, as a result of additional nephrons being induced from the surrounding mesenchyme, and functions as the adult kidney. Despite the fact that vertebrates utilize kidney types of differing organization and complexity, the genes that pattern these organs are highly conserved.4.Dressler G.R. The cellular basis of kidney development.Annu Rev Cell Dev Biol. 2006; 22: 509-529Crossref PubMed Scopus (445) Google Scholar One explanation for this commonality may lie in the fact that their renal structures are composed of a common building block: the nephron. For example, studies of pronephros and metanephros development in various vertebrate models have demonstrated that the transcription factors Wt1 and Pax2 are functionally important for the differentiation of renal progenitors in both kidney types.4.Dressler G.R. The cellular basis of kidney development.Annu Rev Cell Dev Biol. 2006; 22: 509-529Crossref PubMed Scopus (445) Google Scholar As such, the study of pronephros development has been a fruitful avenue to identify and investigate factors that are essential for metanephros development.4.Dressler G.R. The cellular basis of kidney development.Annu Rev Cell Dev Biol. 2006; 22: 509-529Crossref PubMed Scopus (445) Google Scholar, 19.Drummond I.A. Making a zebrafish kidney: a tale of two tubes.Trends Cell Biol. 2003; 13: 357-365Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 20.Jones E.A. Xenopus A prince among models for pronephric kidney development.J Am Soc Nephrol. 2005; 16: 313-321Crossref PubMed Scopus (49) Google Scholar, 21.Reimschuessel R. A fish model of renal regeneration and development.ILAR J. 2001; 42: 285-291Crossref PubMed Scopus (117) Google Scholar, 22.Vize P.D. Seufert D.W. Carroll T.J. et al.Model systems for the study of kidney development: use of the pronephros in the analysis of organ induction and patterning.Dev Biol. 1997; 188: 189-204Crossref PubMed Scopus (166) Google Scholar Amphibian pronephric models, in particular, have provided a system to test gene function using micromanipulation and grafting experiments and assay inductive factors using animal cap explants.20.Jones E.A. Xenopus A prince among models for pronephric kidney development.J Am Soc Nephrol. 2005; 16: 313-321Crossref PubMed Scopus (49) Google Scholar, 22.Vize P.D. Seufert D.W. Carroll T.J. et al.Model systems for the study of kidney development: use of the pronephros in the analysis of organ induction and patterning.Dev Biol. 1997; 188: 189-204Crossref PubMed Scopus (166) Google Scholar In the last decade, the zebrafish model has become a powerful developmental and genetic model. Pioneering work from several research groups has established the zebrafish pronephros as a useful system to study renal development.19.Drummond I.A. Making a zebrafish kidney: a tale of two tubes.Trends Cell Biol. 2003; 13: 357-365Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 23.Hostetter C.L. Sullivan-Brown J.L. Burdine R.D. Zebrafish pronephros: a model for understanding cystic kidney disease.Dev Dyn. 2003; 228: 514-522Crossref PubMed Scopus (28) Google Scholar Like other fish and amphibians, the zebrafish embryo forms a simple pronephros that is comprised of two nephrons that derive from bilateral stripes of IM.19.Drummond I.A. Making a zebrafish kidney: a tale of two tubes.Trends Cell Biol. 2003; 13: 357-365Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 24.Drummond I.A. Majumdar A. Hentschel H. et al.Early development of the zebrafish pronephros and analysis of mutations affecting pronephric function.Development. 1998; 125: 4655-4667Crossref PubMed Google Scholar The anterior-most cells give rise to podocytes that migrate to the midline and recruit endothelial cells to form a single vascularized glomerulus that the two nephrons share.19.Drummond I.A. Making a zebrafish kidney: a tale of two tubes.Trends Cell Biol. 2003; 13: 357-365Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 24.Drummond I.A. Majumdar A. Hentschel H. et al.Early development of the zebrafish pronephros and analysis of mutations affecting pronephric function.Development. 1998; 125: 4655-4667Crossref PubMed Google Scholar, 25.Serluca F.C. Fishman M.C. Pre-pattern in the pronephric kidney field of zebrafish.Development. 2001; 128: 2233-2241PubMed Google Scholar, 26.Majumdar A. Drummond I.A. Podocyte differentiation in the absence of endothelial cells as revealed in the zebrafish avascular mutant, cloche.Dev Genetics. 1999; 24: 220-229Crossref PubMed Scopus (81) Google Scholar, 27.Majumdar A. Drummond I.A. The zebrafish floating head mutant demonstrates podocytes play an important role in directing glomerular differentiation.Dev Biol. 2000; 222: 147-157Crossref PubMed Scopus (44) Google Scholar The remaining IM undergoes a mesenchymal-to-epithelial transition to form a tubular epithelium that fuses at the cloaca, a common exit portal for waste products from the gut and pronephros.18.Zhou X. Vize P.D. Amino acid cotransporter SLC3A2 is selectively expressed in the early proximal segment of Xenopus pronephric kidney nephrons.Gene Expr Patterns. 2005; 5: 774-777Crossref PubMed Scopus (4) Google Scholar, 23.Hostetter C.L. Sullivan-Brown J.L. Burdine R.D. Zebrafish pronephros: a model for understanding cystic kidney disease.Dev Dyn. 2003; 228: 514-522Crossref PubMed Scopus (28) Google Scholar, 24.Drummond I.A. Majumdar A. Hentschel H. et al.Early development of the zebrafish pronephros and analysis of mutations affecting pronephric function.Development. 1998; 125: 4655-4667Crossref PubMed Google Scholar Analysis of several differentiated cell types in the zebrafish pronephros has found similarities with those in the mammalian metanephros. The endothelial cells of the vascular supply are fenestrated, and the podocytes possess extensive interdigitating foot processes.19.Drummond I.A. Making a zebrafish kidney: a tale of two tubes.Trends Cell Biol. 2003; 13: 357-365Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 24.Drummond I.A. Majumdar A. Hentschel H. et al.Early development of the zebrafish pronephros and analysis of mutations affecting pronephric function.Development. 1998; 125: 4655-4667Crossref PubMed Google Scholar At a molecular level, the podocytes express hallmark components of the slit diaphragm, including proteins such as nephrin and podocin.28.Kramer-Zucker A.G. Wiessner S. Jensen A.M. et al.Organization of the pronephric filtration apparatus in zebrafish requires nephrin, podocin and the FERM domain protein mosaic eyes.Dev Biol. 2005; 285: 316-329Crossref PubMed Scopus (159) Google Scholar These similarities to mammalian nephrons make the zebrafish pronephros a relevant and convenient tool for renal physiology studies.6.Anzenberger U. Bit-Avragim N. Rohr S. et al.Elucidation of megalin/LRP2-dependent endocytic transport processes in the larval zebrafish pronephros.J Cell Sci. 2006; 119: 2127-2137Crossref PubMed Scopus (51) Google Scholar, 29.Kramer-Zucker A.G. Olale F. Haycraft C.J. et al.Cilia-driven fluid flow in the zebrafish pronephros, brain, and Kupffer's vesicle is required for normal organogenesis.Development. 2005; 132: 1907-1921Crossref PubMed Scopus (481) Google Scholar In addition, defects in genes associated with polycystic kidney diseases in humans lead to pronephros cyst formation in zebrafish, highlighting the usefulness of fish to study this type of disorder.23.Hostetter C.L. Sullivan-Brown J.L. Burdine R.D. Zebrafish pronephros: a model for understanding cystic kidney disease.Dev Dyn. 2003; 228: 514-522Crossref PubMed Scopus (28) Google Scholar, 30.Sun Z. Amsterdam A. Pazour G.J. et al.A genetic screen in zebrafish identifies cilia genes as a principle cause of cystic kidney.Development. 2004; 131: 4085-4093Crossref PubMed Scopus (404) Google Scholar, 31.Sun Z. 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Obara T. et al.Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination.Nat Genet. 2003; 24: 413-420Crossref Scopus (478) Google Scholar Until recently, it was thought that the one major drawback of the zebrafish pronephros as a model for studying nephron formation was the simple organization of the tubule itself. There was initially no evidence that the pronephric tubule was specialized into the prototypical series of proximal and distal segments that exist in metanephric nephrons. Indeed, only a short stretch of tubule was thought to exist in the pronephros, connecting the glomerulus to a long pronephric duct (see inset, Figure 1b). In the last few years, however, several reports suggested the existence of subdomains within the zebrafish pronephric duct.6.Anzenberger U. Bit-Avragim N. Rohr S. et al.Elucidation of megalin/LRP2-dependent endocytic transport processes in the larval zebrafish pronephros.J Cell Sci. 2006; 119: 2127-2137Crossref PubMed Scopus (51) Google Scholar, 7.McCarthy R.A. Barth J.L. Chintalapudi M.R. et al.Megalin functions as an endocytic sonic hedgehog receptor.J Biol Chem. 2002; 277: 25660-25667Crossref PubMed Scopus (146) Google Scholar, 8.Nichane M. Van Campenhout C. Pendeville H. et al.The Na+/PO4 cotransporter slc20a1 gene labels distinct restricted subdomains of the developing pronephros in Xenopus and zebrafish embryos.Gene Expr Patterns. 2006; 6: 667-672Crossref PubMed Scopus (25) Google Scholar, 9.Van Campenhout C. Nichane M. Antoniou A. et al.Evi1 is specifically expressed in the distal tubule and duct of the Xenopus pronephros and plays a role in its formation.Dev Biol. 2006; 294: 203-219Crossref PubMed Scopus (33) Google Scholar For example, the expression domains of the solute transporter slc4a4 and the endocytic receptor megalin/lrp2 were found to be restricted within the anterior-most portion of the pronephric duct.6.Anzenberger U. Bit-Avragim N. Rohr S. et al.Elucidation of megalin/LRP2-dependent endocytic transport processes in the larval zebrafish pronephros.J Cell Sci. 2006; 119: 2127-2137Crossref PubMed Scopus (51) Google Scholar, 7.McCarthy R.A. Barth J.L. Chintalapudi M.R. et al.Megalin functions as an endocytic sonic hedgehog receptor.J Biol Chem. 2002; 277: 25660-25667Crossref PubMed Scopus (146) Google Scholar, 8.Nichane M. Van Campenhout C. Pendeville H. et al.The Na+/PO4 cotransporter slc20a1 gene labels distinct restricted subdomains of the developing pronephros in Xenopus and zebrafish embryos.Gene Expr Patterns. 2006; 6: 667-672Crossref PubMed Scopus (25) Google Scholar, 9.Van Campenhout C. Nichane M. Antoniou A. et al.Evi1 is specifically expressed in the distal tubule and duct of the Xenopus pronephros and plays a role in its formation.Dev Biol. 2006; 294: 203-219Crossref PubMed Scopus (33) Google Scholar However, both of these genes mark specific proximal tubule segments in metanephric nephrons.35.Endo Y. Yamazaki S. Moriyama N. et al.Localization of NBC1 variants in rat kidney.Nephron Physiol. 2006; 104: 87-94Crossref Scopus (13) Google Scholar, 36.Christensen E.I. Birn H. Megalin and cubulin: multifunctional endocytic receptors.Nat Rev Mol Cell Biol. 2002; 3: 258-268Crossref Scopus (603) Google Scholar Thus, these results challenged the notion that the region of the zebrafish pronephros historically regarded as duct might actually be tubule-like in nature. To investigate this possibility, our laboratory used a functional genomics-based strategy to isolate markers of differentiated renal cell types in zebrafish. From this approach, a number of genes were identified whose expression in the pronephros was restricted to one or more particular subdomains.10.Wingert R.A. Selleck R. Yu J. et al.The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros.PLoS Genet. 2007; 3: e189Crossref Scopus (212) Google Scholar In total, the zebrafish pronephros was found to contain at least eight discrete regions10.Wingert R.A. Selleck R. Yu J. et al.The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros.PLoS Genet. 2007; 3: e189Crossref Scopus (212) Google Scholar (Figure 1b). The expression profile of these regions likens them to many of the segments that exist in metanephric nephrons10.Wingert R.A. Selleck R. Yu J. et al.The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros.PLoS Genet. 2007; 3: e189Crossref Scopus (212) Google Scholar (Figure 2). Based on this comparison, we redefined the organization of the pronephros. What was previously considered the tubule portion of the pronephros was reclassified as a neck segment, whereas the long stretch of tubular epithelium that has traditionally been considered duct was subdivided into two proximal tubule segments, two distal tubule segments, and a short duct.10.Wingert R.A. Selleck R. Yu J. et al.The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros.PLoS Genet. 2007; 3: e189Crossref Scopus (212) Google Scholar The zebrafish neck segment expresses rfx2, an established marker of ciliated cells, suggesting that it is ciliated similar to the neck segment found in a number of mammals, including humans.1.Hebert S.C. Reilly R.F. Kriz W. Structural–functional relationships in the kidney.in: Schrier R.W. Diseases of the Kidney and Urinary Tract. 7th edn. Lippincott Williams and Wilkens, Philadelphia2001: 3-57Google Scholar, 10.Wingert R.A. Selleck R. Yu J. et al.The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros.PLoS Genet. 2007; 3: e189Crossref Scopus (212) Google Scholar The PCT and PST express genes found throughout the proximal tubule of mammals, like slc9a3.10.Wingert R.A. Selleck R. Yu J. et al.The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros.PLoS Genet. 2007; 3: e189Crossref Scopus (212) Google Scholar The PCT segment undergoes morphogenesis beginning at 2 dpf to form a coiled loop on each side of the glomerulus, whereas the PST segment remains linear, morphologies similar to their mammalian counterparts. Transcripts for megalin are confined to the PCT domain in zebrafish (RAW and AJD, unpublished data), where megalin has been shown to perform metabolite recovery via endocytosis,6.Anzenberger U. Bit-Avragim N. Rohr S. et al.Elucidation of megalin/LRP2-dependent endocytic transport processes in the larval zebrafish pronephros.J Cell Sci. 2006; 119: 2127-2137Crossref PubMed Scopus (51) Google Scholar analogous to its role in the mammalian PCT. The zebrafish PST segment expresses the mammalian PST marker slc13a3 in a discontinuous pattern that reflects the presence of muliticiliated and transporting cells.10.Wingert R.A. Selleck R. Yu J. et al.The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros.PLoS Genet. 2007; 3: e189Crossref Scopus (212) Google Scholar, 37.Ma M. Jiang Y.J. Jagged2a-Notch signaling mediates cell fate choice in the zebrafish pronephric duct.PLoS Genet. 2007; 3: e18Crossref PubMed Scopus (99) Google Scholar, 38.Liu Y. Pathak N. Kramer-Zucker A. et al.Notch signaling controls the differentiation of transporting epithelia and multiciliated cells in the zebrafish pronephros.Development. 2007; 134: 1111-1122Crossref PubMed Scopus (148) Google Scholar Interestingly, immunostaining with the Xenopus 3G8 antibody, which detects the brush border, appears to label the region encompassing both proximal segments,24.Drummond I.A. Majumdar A. Hentschel H. et al.Early development of the zebrafish pronephros and analysis of mutations affecting pronephric function.Development. 1998; 125: 4655-4667Crossref PubMed Google Scholar suggesting that they possess the apical microvilli that are a structural characteristic of the mammalian proximal tubule.1.Hebert S.C. Reilly R.F. Kriz W. Structural–functional relationships in the kidney.in: Schrier R.W. Diseases of the Kidney and Urinary Tract. 7th edn. Lippincott Williams and Wilkens, Philadelphia2001: 3-57Google Scholar Following the proximal segments in the zebrafish is a distal region, marked by expression of clck, which includes the distal early (DE), distal late (DL), and pronephric duct (PD) segments. The DE exclusively expresses slc12a1, which specifically marks the thick ascending limb segment in mammals, whereas the DL expresses slc12a3, which is uniquely expressed in the mammalian distal convoluted tubule segment.10.Wingert R.A. Selleck R. Yu J. et al.The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros.PLoS Genet. 2007; 3: e189Crossref Scopus (212) Google Scholar These observations suggest that the DE and DL are analogous to the mammalian thick ascending limb and distal convoluted tubule, respectively.10.Wingert R.A. Selleck R. Yu J. et al.The cdx genes and retinoic aci
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