Jagged notch signaling in zebrafish pronephros development

Chapter I: Introduction 1.1 Kidney Function and Development 1.1.1 Kidney Function and Mammal Kidney Development The kidney is a complex organ that regulates blood homeostasis through the maintenance of fluid and ion balance and disposal of metabolic waste (Saxen, 1987) In mammals, development of the excretory system is characterized by the successive formation of three distinct kidneys with increased complexity: pronephros, mesonephros and metanephros The pronephros derives from the intermediate mesoderm, which lies between paraxial mesoderm and lateral plate mesoderm The mammalian pronephros is a non-functional transitory structure that is replaced by the mesonephros and then the metanephros The permanent functional kidney, the metanephros, begins to form in the mouse at ~11 days post coitum (dpc) when a collection of mesenchymal cells (the metanephric blastema) induces an outgrowth from the Wolffian duct (mesonephric duct) called the ureteric bud, which invades the metanephric mesenchyme (or blastema) (Saxen and Sariola, 1987) The ureteric epithelium then induces adjacent mesenchymal cells to condense and to epithelialize, forming the renal vesicle (Schedl and Hastie, 2000) Concomitantly, the mesenchymal derivatives induce branching and growth of the ureteric bud This process of reciprocal induction continues at the periphery to form new nephrons and new ureteric bud branches in the mouse until 1-2 weeks after birth, resulting in ~15,000 nephrons per kidney The renal vesicle differentiates and alters its morphology to form comma- and then S-shaped bodies, from which arise the nephrons that consist of glomerulus, proximal tubule and distal tubule The ends of the distal tubules fuse with the inducing branches of the ureteric bud, which give rise to the collecting ducts (Saxén, 1987; Serluca and Fishman, 2001); each of the segments has a different function The glomerulus is the site of blood filtration Epithelia of the tubules are the primary sites of selective reabsorption and secretion, whereas the duct carries the modified urine to the outside world (Saxén, 1987) Though quite uniform in appearance, the tubule and duct epithelia are further subdivided into distinct segments, recognized by the expression of specific membrane transporters This is a general feature of vertebrate kidneys, where osmoregulatory function depends on an organized disposition of different transporters operating sequentially along the nephron (Tenenhouse et al., 1998; Vize 2003) 1.1.2 Signaling and Transcription Factors that Control Kidney Development 1.1.2.1 Patterning of Nephric Mesoderm by Bmp Signals from Ventral Ectoderm The intermediate mesoderm lies between the somites and the lateral plate and is the source of all kidney tissue in the developing vertebrate embryos; intermediate mesoderm and lateral plate mesoderm are at the ventral side of the axis Through micro-surgery, tissue culture and in situ RNA hybridization analysis, it was demonstrated that Bmp signals from ventral ectoderm pattern the mesoderm for different fates, including the nephric mesoderm (Obara-Ishihara et al., 1999); Bmp signaling promotes intermediate mesoderm genes expression (Odd1, Pax2, Pax8 and Lim1) in a dose-dependent, cell-autonomous and translation-dependent manner (James and Schultheiss, 2005) 1.1.2.2 Pax2/8 in Kidney Development Pax genes are important developmental regulators that function at multiple stages of vertebrate kidney organogenesis In vertebrates, the pax2, pax5 and pax8 genes have been grouped into a common subfamily based on their sequence similarity and expression pattern pax2/pax5/pax8 members encode proteins that have common the paired domain, an octapeptide motif, and a partial homeodomain Nephric lineage was specified by Pax2 and Pax8 from mesoderm in mouse (Bouchard et al., 2002) Mouse embryos lacking both Pax2 and Pax8 are unable to form the pronephros or any later nephric structures In these double-mutant embryos, the intermediate mesoderm forms, but does not undergo the mesenchymal-epithelial transitions required for nephric duct formation, failing to initiate the kidney-specific expression of Lim1 and c-Ret, and is lost by apoptosis one day after failed pronephric induction The Pax2 gene is expressed during multiple stages of vertebrate nephrogenesis and is mutated in human genetic diseases of the genitourinary system (Dressler et al., 1990, 1993; Krauss et al., 1991; Puschel et al., 1992; Sanyanusin et al., 1996; Dressler and Woolf, 1999) Mice homozygous for a null mutation in Pax2 display severe defects in genitourinary development (Torres et al., 1995) Specifically, the Wolffian, or pronephric, duct degenerates before it is completely formed, resulting in kidney agenesis thus demonstrating a critical role for this gene in early stages of nephrogenesis In addition to its role in pronephric duct growth, Pax2 is likely to function in later stage of kidney development During metanephric development, Pax2 is expressed strongly in the branching ureteric bud and in command S-shaped mesenchymal condensations, suggesting a role for Pax2 during nephron differentiation and morphogenesis (Dressler et al., 1990; Ryan et al., 1995) Deregulated expression of Pax2 in transgenic mice impedes tubular and glomerular differentiation and results in kidney cysts, implying that temporal and spatial control of Pax2 expression is important for proper renal epithelial differentiation (Dressler et al., 1993) In addition, antisense oligonucleotides directed against Pax2 interfere with nephron differentiation in organ culture (Rothenpieler and Dressler, 1993) 1.1.2.3 Odd Skipped Related Genes in the Kidney Development In mammalian genomes, two odd skipped related genes (Odd1 and Odd2) were found, both of which were expressed dynamically during the kidney formation (So and Danielian 1999; Lan et al., 2001) Mouse Odd1 is the mammalian odd-skipped related and it is the earliest transcription factor expressed in the nephric mesoderm (James and Schultheiss, 2005) Through analysis of Odd1 knockout mice, Odd1 is essential for the formation and differentiation kidney precursor cells (metanephric mesenchyme) (Wang et al., 2005; James et al., 2006) Odd2 knockout mice did not exhibit detectable defects in kidney tissues (Lan et al., 2004) 1.1.2.4 Differentiation (Segmentation) of the Nephron by Signaling and Transcription Factors Morphogenesis and cell fate determination of different nephric segments have attracted much attention recently Multiple transcription factors and signaling pathways have been shown to be involved in these processes in different model organisms These include Foxc2 for the differentiation of podocyte in glomerulus (Takemoto et al., 2006), Brn1 is required for the development of Henle’s loop, distal convoluted tubule and the macula densa in mice at primitive loop stage (Nakai et al., 2003) Some segments of the nephron comprise only one cell type, while others include two or more cell types The mammalian collecting duct contains two major cell types: principal cells (for salt and water absorption) and intercalated cells (for acid/base transport) (Al-Awqati and Schwartz, 2004) It was reported that Foxi1 plays a crucial role in the specification of intercalated cells (Blomqvist et al., 2004) Proximal tubule is the segment that is most intensively studied and multiple signaling including Notch signaling and transcription factors have been demonstrated to be required for the tubule cell development from different model organism These include Wnt-4 for the tubule cell fate in mouse and Xenopus (Stark et al., 1994; Saulnier et al., 2002) Mouse Pax2 localizes to the proximal tubule and activates Wnt-4 expression in the proximal tubule (Torban et al., 2006) In Xenopus, Fgf signaling was found to be regulated by Shh signaling and required for tubule condensation and mesenchymal-epithelial transition (Urban et al., 2006) 1.2 Zebrafish, a Model for Vertebrate Development and Diseases, Including Organogenesis Zebrafish has gradually become a good model organism for studying early vertebrate development during the past decade It has the following advantages over other vertebrate model organisms, such as frog or mouse Zebrafish embryos develop outside of the mother’s body and the embryos are optically transparent throughout early development, thus making many of organs extremely easy to observe Zebrafish embryos develop rapidly, taking one day to develop from fertilized egg to an embryo with a typical vertebrate body plan with a neural tube, a beating heart, and musculature system; it takes two days for the embryos to reach free-swimming larvae with blood circulation and functional kidney (filteration occurs within two days) It has a relatively short generation time, taking 3-4 months for zebrafish to reach sexual maturity Finally, Zebrafish are small and therefore it is economical to maintain large number of fish lines and it is able to produce large clutches of embryos (100-200 per mating per week) Therefore, forward genetics have been used extensively to isolate many mutants (comparable experiments are very difficult using mammalian embryos) 1.2.1 Genetics in zebrafish 1.2.1.1 Forward Genetics Forward genetics is a powerful approache for finding gene function Two methods of mutagenesis have been used to isolate mutants: N-ethyl-N-nitrosourea (ENU), which mainly causes point mutations to the genome, or retrovirus, which can integrate to the genome and disrupt gene function ENU has been shown to efficiently cause unbiased point mutations in the genome Through several large scale screening in 1996 and 2000, (Haffter et al., 1996; Driever et al., 1996; Tübingen 2000 Screen Consortium), thousands mutants were recovered These include dorso-ventral patterning mutants, germ layer specification defective mutants, organogenesis impaired mutants, neural defect mutants, cell migration defect mutants Even though the efficiency of the retroviral integration to the genome is less efficient than that of ENU-mutagenesis, however, the cloning of the mutant (inserted and disrupted) gene is very efficient with Tail-PCR Hundreds of mutants with defects in various developments were recovered from a big genetic screenings (Golling et al., 2002) 1.2.1.2 Reverse Genetics: TILLING and Morpholino-antisense Knock Down Technique Reverse genetics is also possible through the “Targeting-induced local lesions in genes” TILLING method, in that the mutations on a specific “target” gene of interest can be identified by genomic sequence analysis of the F1 progenies of ENU mutagenized parents Through TILLING, Wienholds and colleagues isolated 15 rag1 mutations (Wienholds et al., 2002) and mutations in microRNA-producing enzyme, dicer1 (Wienholds et al., 2003) Alternatively morpholino modified antisense-oligo-nucletides have been shown to be able to specifically and efficiently block the translation of the target transcripts, thus generating a “knockdown” effect, which can last for at least the first fifty hours of development (Nasevicius and Ekker, 2000) Alternately, morpholino modified anti-sense could be designed to target exon-intron junctions to block the splicing of pre-mRNA, thus knocking down the gene function Moreover, RT-PCR could be employed to monitor the efficacy of blocking of splicing pre-mRNA (Draper et al., 2001) 1.2.1.3 Transgenesis Zebrafish transgenesis works well Tissue specific promoter-driven GFP or dsRed allow tracing of specific cell groups and visualization of cell migration For example, fli promoter-driven GFP could make all vasculature visible under the fluoresent microscope and allow the analysis of the dynamics of vasculagenesis (Isogai et al., 2001) Moreover, the tissue specific transgenic fish could be used as founders to make the tissue easier to be identified in the genetic screening (review in Udvadia and Linney, 2003) A common way to analyze the function of genes in zebrafish is to misexpress the gene product by mRNA injection However, mRNA injection has several disadvantages: mRNA start to be translated to protein immediately after it its injectd to the egg and it will be activated in almost all the cells in the embryo and the gene function activation is not in a spatial and temporal controlled way, thus make the results difficult to interprete Some gene products are toxic to the development of early embryo and will arrest the embryo development in early stage, making the analysis of gene function in late development impossible mRNA decay is quite fast and it difficult to analysis gene function in the late stage Tissue specific promoter drived GAL4 (yeast transcriptional activator) and UAS (DNA-binding motif of GAL4) fused with target gene method has been used extensively to study the gain of function of a gene in a spatial-and-temporal-controlled manner in Drosophila UAS/Gal4 system has been demonstrated to be effective in the zebrafish (Scheer and Campos-Ortega, 1999, Scheer et al., 2002) By using heat-shock promoter drived GAL4 and UAS fused with Notch intra-cellular domain, Notch signaling was demonstrated to promote gliogenesis in retina of the zebrafish (Scheer et al., 2001) 1.2.2 Manipulation of Zebrafish Embryos Zebrafish embryo is transparent and make it easy to be observed and manipulated Transplantation of single cell or group of cells to the host embryos and allow the observation of mutant cells behave in wildtype embryos or wildtype cells behave in mutant embryos and these experiment will tell whether certain gene products act cell autonomously or cell non-autonomously Uncaging experiments allow the trace of the lineage of the cells (Kozlowski et al., 1997) By uncaged the GFP labeled hemotopeiotic stem cell in the early stage, Jin and co-workers demonstrated that hemotopeitic stem cell migrate from ventral wall of dorsal aorta to posterior blood island and finally to the final hematopoeistic organ kidney (Jin et al., 2007) 1.3 Zebrafish Pronephros: a Kidney Development and Diseases Model In contrast to that of higher vertebrates, whose pronephros is a transient non-functional organ, the pronephros of fish and amphibians in their early life is a functional filtration organ that develops very similarly to metanephros, and has been used as a model for kidney development While metanephroi of the mammals have millions of nephrons, pronephroi in fish and amphibians contain two functional nephrons (Saxén, 1987; Vize et al., 1995; Drummond et al., 1998) Embryonic kidney (pronephros) organogenesis in fish and amphibian can be viewed as occurring in four general stages or developmental events 1) The early patterning of the mesoderm to intermediate or nephrogenic mesoderm during gastrulation 2) Formation of nephric primordium (mesenchymal to epithelial transition) during somitogenesis 3) Patterning of nephron primordia into distinct segments: glomerulus, tubule and duct 4) Vascularization of the glomerulus and the onset of blood filtration 1.3.1 Bmp signaling and Odd1 are essential for patterning IM of zebrafish Bmp signaling from ventral ectoderm has been demonstrated in promoting intermediate mesoderm development in chick (Obara-Ishihara et al, 1999; James and Schultheiss, 2005) Bmp signaling is also essential for the IM patterning in zebrafish and the evidence is from analysis of Bmp pathway mutants swirl(bmp2b-/-) and snailhouse(bmp7-/-) Ventral mesoderm is lost in these mutants (Mullins et al., 1996) Moreover, by using transgenic zebrafish carrying hsp70 driven Xenopus dominant-negative Bmp receptor 1a (intra-cellular domain replaced with GFP) (Tg hsp70:dnXBmpr1a-GFP) to conditionally interfere with Bmp function, ventral mesoderm, including intermediate mesoderm, was found to be specified during early gastrulation, while Bmp signaling was not required for the specification afterwards (Pyati et al., 2005) A recent study revealed that both odd1 were expressed in the IM in zebrafish and odd1 act as repressors and is essential for the formation of zebrafish pronephros (Tena et al., 2006) 1.3.2 Zebrafish Pronephros is Pre-patterned and Segmented The zebrafish pronephros consists of paired glomeruli coalescing at the midline ventral to the dorsal aorta, and two pronephric tubules that project bilaterally from the glomeruli to the pronephric ducts that run caudally and fuse just before their contact with the exterior at the cloaca (Drummond et al., 1998) (Figure 1.1) The zebrafish pronephros is pre-patterned and anterior, middle and posterior intermediate mesoderm (IM) gives rise to glomerulus, tubule and duct, respectively (Serluca and Fishman, 2001) Zebrafish pronephric duct is further sub-divided and expresses different transporters, even though these ductal sub-domains are not morphologically distinguishable (Nichane et al., 2006) Through expression and functional analysis of the endocytic receptor/co-receptors with morpholino knockdown technique, Anzenberger and co-workers (2006) demonstrated that the primary segment for the clearance of metabolite of glomerular filtrate is the proximal pronephric duct, rather than that of the proximal tubule as in mammals (Anzenberger et al., 2006) 1.3.3 Pax2a/Pax8 are Essential for Mesencymal-to-Epithelial Transition and Many Other Steps for Zebrafish Pronpehros Development Zebrafish pax2a is the orthologue of mammal Pax2 and pax2a is important in multiple aspects of zebrafish pronephric development through analysis of pax2a mutant no isthmus (noi) Pronephric duct cell polarity is disrupted, suggesting that the mesenchymal to epithelial transition is defective in noi mutant; moveover, tubule cells are lost and cloaca morphogenesis is defective in noi fish (Brand et al., 1996; Majumdar et al., 2000) Similar to mammalian Pax8, pax8 is also expressed in the pronephros and its expression starts from late gastrulation stage, which is earlier than that of pax2a in the pronephros, which starts to express at tailbud stage (Pfeffer et al., 1998) 1.3.4 Zebrafish Pronephros Serves as a Model for Human Kidney Diseases Through ENU-mutagenesis screening for kidney development mutants, 13 mutants were recovered These mutants have different cyst formation at the tubule and/or glomerulus associated with or without body axis curvature (Drummond et al., 1998) More recently, an insertional mutagenesis screening in zebrafish identified 12 genes whose mutations cause cysts in the glomerular-tubular region Subsequent molecular characterization revealed that many of them were cilia (flagella) genes and one is pkd2 (polycystoc kidney diseases), which has already been associated with human cystic kidney diseases (Sun et al., 2004) Another mutant fish with cystic kidney was found to have the lesion at the vHnf1 gene Mutations in the human homeobox gene vHnf1 are associated with maturity-onset diabetes of the young, type V (MODY5) and familial glomerulocystic kidney disease (GCKD) (Sun and Hopkins 2001; Sun et al., 2004) These mutants could serve as good model for investigating the etiology of human diseases and for screening for therapeutic reagents (small molecules) to cure the diseases Indeed, some efforts have been put to screen for drugs to cure human disease with zebrafish model (MacRae and Peterson, 2003; Hong et al., 2006) 1.4 Notch Signaling: Regulation of Notch Signaling and Function in Kidney 1.4.1 Notch Signaling: Lateral Inhibition and Lateral Induction Notch signaling is an evolutionarily conserved pathway that multicellular animals use in regulating pattern formation and cell fate determination through local cell interactions (Artavanis-Tsakonas et al., 1999) One of its best known roles is in selecting cells to become neuroblasts or sensory organ precursors in Drosophila by the process of lateral inhibition, where cells acquire a neural fate by inhibiting their neighbors from adopting a similar fate Cells in proneural clusters initially acquire the potential to adopt a neural fate 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