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Transcriptional regulators in kidney disease: gatekeepers of ...

  1. 1. TIGS-649; No of Pages 11 Review Transcriptional regulators in kidney disease: gatekeepers of renal homeostasis N. Henriette Uhlenhaut and Mathias Treier Developmental Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany Although we are rapidly gaining a more complete associated with the development of glomerulosclerosis understanding of the genes required for kidney function, or interstitial fibrosis that result from the reversal of the molecular pathways that actively maintain organ developmental processes that were originally used to build homeostasis are only beginning to emerge. The study the kidney. Therefore, some of the pathophysiological of the most common genetic cause of renal failure, polycystic kidney disease, has revealed a surprising role for primary cilia in controlling nuclear gene expression Glossary and cell division during development as well as main- Anosmia: absence of the ability to smell. tenance of kidney architecture. Conditions that disturb Autosomal dominant polycystic kidney disease (ADPKD): hereditary disorder characterized by the presence of multiple fluid-filled cysts inside enlarged kidneys; kidney integrity seem to be associated with reversal of cysts arise from all nephron segments. developmental processes that ultimately lead to kidney Autosomal recessive polycystic kidney disease (ARPKD): recessively inherited disease similar to ADPKD, but cysts derive primarily from dilation of the collecting fibrosis and end-stage renal disease (ESRD). In this tubule. review, we discuss transcriptional regulators and net- Bardet-Biedl syndrome (BBS): human genetic disorder including kidney abnorm- works that are important in kidney disease, focusing alities, retinal degeneration, mental retardation, obesity, diabetes, polydactyly and situs inversus. on those that mediate cilia function and drive renal Chronic kidney disease (CKD): progressive decline of kidney function, leading to fibrosis. kidney failure. Collecting duct: epithelial tubes derived from the branched ureteric bud, draining Chronic kidney disease: an emerging pandemic health the urine from the nephrons into the renal papilla. End-stage renal disease (ESRD): kidney failure (the need for dialysis). problem Epithelial-to-mesenchymal transition (EMT): process during which epithelial cells Our kidneys serve important physiological functions to acquire mesenchymal, fibroblast-like properties (with reduced intercellular adhe- sion and increased motility); the reverse process is called mesenchymal-to- excrete waste products from the body and balance the body epithelial transition (MET). fluids. Disturbance in the renal filtration process can pose a Fibrosis: formation of scar (fibrous) tissue. serious health threat. Currently, 10% of the global adult Glomerulosclerosis: scarring of the glomerulus, which impairs the filtration process; often observed in chronic kidney disease. population, regardless of ethnic origin, are affected by Glomerulus: a small group of looping blood vessels surrounded by Bowman’s chronic kidney disease. An estimated 1.5 million patients capsule where the blood is filtered and urine is formed; consists of podocytes, are dependent on renal replacement therapy [1,2]. endothelial and mesangial cells; see Figure I. Lymphedema-Distichiasis syndrome: a condition that affects the function of the For many years, the kidney has been a classical model lymphatic system resulting in extra eyelashes and tissue swelling. for studying organogenesis (see Boxes 1 and 2 for a brief Mesangial cells: supportive cells within the glomerulus. overview). Research on human genetic disorders associ- Metanephric mesenchyme (MM): an aggregate of mesenchymal cells in the embryo from which renal stroma and nephrons originate. ated with renal malfunction, in conjunction with the Nephron: the basic functional unit of the kidney, consisting of glomerulus, analysis of gene disruption studies in mice and other model proximal tubule, loop of Henle, distal tubule, and collecting duct. organisms, has led to the identification of many transcrip- Nephronophthisis (NPHP): autosomal recessive disorder affecting juveniles; progressive deterioration of kidney function, with medullary cysts, tubular tion factors required for kidney development and homeo- degeneration and fibrosis. Phthisis (Greek) = a dwindling or wasting away. stasis (Box 2). Despite the wealth of information available, Nephropathy: kidney disease. we are still far from an integrative picture of the regulatory Podocyte: epithelial cells in the glomerulus that form part of the filtration barrier. Polyuria: excessive excretion of urine. networks that maintain the integrity of the mature kidney. Proteinuria: protein in the urine, a sign of renal dysfunction. Modulation of signaling pathway strength by extrinsic Renal agenesis: absence of kidneys caused by a developmental defect. Renal dysplasia: abnormal development of the kidneys (with regard to size and factors results in gene expression program changes that shape). precede the observed morphological alterations in chronic Renal replacement therapy: life-supporting treatments for renal failure, such as kidney disease. Thus, understanding the transcriptional dialysis and kidney transplantation. Renal tubule: the elongated, tube-like part of the nephron, made up of the promixal networks that maintain cell type identity in the mature and distal convoluted tubules and the loop of Henle. kidney provides a promising entry point for future thera- Situs inversus: a condition in which the inner organs are arranged in a perfect peutic interventions [3]. Many forms of chronic kidney mirror image reversal of the normal positioning Slit diaphragm: transmembrane structure between podocyte foot processes disease (i.e. diabetic nephropathy, nephronophthisis) are creating a sieve. Ureteric bud: epithelial protrusion (outpouching) from the Wolffian/nephric duct that invades the metanephric mesenchyme during kidney development and gives rise to the collecting duct system. Corresponding author: Treier, M. ( 0168-9525/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tig.2008.05.001 Available online xxxxxx 1
  2. 2. TIGS-649; No of Pages 11 Review Trends in Genetics No.x Table 1. Transcription factors associated with human renal disease Gene Murine kidney phenotype Human syndrome OMIM EYA1 Agenesis, no metanephric mesenchyme specified Bbranchio-otorenal syndrome: hearing loss, ear pits, branchial cysts 601653 or fistulas, kidney anomalies a FOXC1 Positioning of ureteric bud affected Axenfeld-Rieger syndrome (congenital ocular disorder) and 601090 congenital anomalies of the kidney and urinary tract a FOXC2 Kidney hypoplasia, glomerular defects, ureteric bud Lymphedema-Distichiasis syndrome with renal disease and diabetes 602402 positioning affected mellitus a GATA3 No ureteric branching, no metanephric differentiation HDR syndrome: hypoparathyroidism, sensorineural deafness and 131320 renal disease a GLI3 Expression of a truncated instead of full-length Gli3 Pallister-Hall syndrome: fingers and toes affected, benign 165240 protein mimics Pallister-Hall syndrome; kidney hypothalamic tumors, associated with renal anomalies (and others) a development is abnormal GLIS2 Kidney degeneration and cysts Nephronophthisis 608539 GLIS3 Polycystic kidneys Diabetes mellitus, hypothyroidism and polycystic kidneys 610192 HNF1b Cystic kidneys Renal cysts and diabetes syndrome 189907 LMX1b Impaired podocyte differentiation Nail Patella syndrome, including nephropathy a 602575 NFIA Ureteral and renal defects Central nervous system malformations and urinary tract defects a 600727 PAX2 Agenesis, nephric duct is not maintained Renal-Coloboma syndrome: optic nerve abnormalities, 167409 vesicoureteral reflux and renal hypoplasia a SALL1 Agenesis, no ureteric bud outgrowth Townes-Brocks syndrome: abnormalities in thumbs, feet, heart, ears 602218 (impaired hearing), kidney; imperforate anus a SALL4 Renal hypoplasia (agenesis in Sall1/Sall 4 compound Duane-Radial Ray (or Okihiro) syndrome associated with kidney 607343 heterozygotes) defects a SIX1 No ureteric bud invasion, metanephric mesenchyme Branchio-otorenal) syndrome a 601205 is not sustained SIX5 Unknown Branchio-otorenal) syndrome a 600963 WT1 No kidneys Wilm’s tumor, Wilm’s tumor-aniridia-genitourinary anomalies- 607102 mental retardation syndrome, Denys-Drash syndrome, Frasier syndrome, diffuse mesangial sclerosis a a In humans, many of these syndromes are caused by haploinsufficiency, whereas the phenotype of many mouse mutants only manifests itself in the homozygous situation. processes observed in chronic kidney disease are better proteins has led to the unifying theory that polycystic kidney understood in light of normal kidney development. Sur- diseases are associated with a defect in primary cilia func- prisingly, many transcriptional regulators that when tion [5,6]. mutated cause congenital abnormalities of the kidney, such Nearly all nondividing cells of the body extend a single as renal agenesis, renal hypoplasia, dysplasia or uretic primary, nonmotile cilium into the extracellular space. malformations, are reactivated during chronic kidney dis- Primary cilia are sensory organelles involved in photore- eases (summarized in Table 1 and Box 2; for a review, see ception, olfaction and mechanosensation. They consist of a Ref. [4]). central axoneme built of microtubules, covered by a Here we focus on emerging evidence that suggests that specialized plasma membrane. Ciliary function depends developmental gene expression programs are reactivated on intraflagellar transport (IFT) along their microtubules, in chronic renal disease, pointing toward an underappre- because there is no protein synthesis within the cilium ciated cellular plasticity of renal cells. Furthermore, we itself [7,8] (Figure 1). discuss recent findings that localization and processing of The membrane proteins encoded by PKD1, PKD2 and transcriptional regulators at the cilium are crucial for the PKHD1 as well as the NPHP and Bardet-Biedl-syndrome maintenance of kidney homeostasis. (BBS) proteins localize to primary cilia and/or basal bodies or centrosomes. Consequently, mislocalisation of these Cystic kidney diseases are ciliopathies proteins caused by absence of renal cilia or disruption of Cystic renal diseases are the most common genetic cause of cilia function causes cyst formation [5]. Elegant genetic end-stage renal disease (ESRD) [2]. Among children, experiments in adult mice using a tamoxifen-inducible Cre nephronophthisis (NPHP) and autosomal recessive polycys- recombinase system have shown that loss of cilia through tic kidney disease (ARPKD) are predominant, whereas disruption of IFT leads to slow onset cystic kidney disease autosomal dominant polycystic kidney disease (ADPKD) [9]. A similarly designed study that induced PKD1 inacti- prevails among adults. Mutations in the polycystin-1 vation in the mature kidney reported the same findings (PKD1) and polycystin-2 (PKD2) genes are responsible for [10]. Although the progression of the disease phenotype in most ADPKD cases, whereas PKHD1 mutations account both cases was less aggressive than that observed after predominantly for ARPKD. The major steps of early kidney disruption of IFT or PKD1 during development, these development proceed normally in patients with polycystic results nevertheless suggest that cilia function is required kidney disease, but terminal differentiation (i.e. the epi- to actively maintain kidney architecture throughout life. thelial morphology of renal cells) cannot be sustained, In addition to polycystic kidney disease, people with resulting in the functional tubular architecture being dis- cilia-associated genetic disorders often present with rupted by fluid-filled cysts. Several genes responsible for retinal degeneration, liver cysts and fibrosis, anosmia, cyst development have been identified by positional cloning situs inversus and systemic phenotypes such as obesity, in human patients, and the subsequent study of these diabetes, heart defects, hypertension, as well as skeletal 2
  3. 3. TIGS-649; No of Pages 11 Review Trends in Genetics No.x and neurological defects [11]. Dysfunction of motile cilia These studies have illuminated the molecular mechanisms such as the sperm’s flagellum or the ones lining our air- downstream of Hh signaling in kidney development and ways and fallopian tubes can lead to laterality defects, can explain the malformations found in Pallister-Hall respiratory problems, infertility and hydrocephalus [6]. syndrome that are thought to be caused by expression of a dominant-negative GLI3 repressor. The function of the cilium in hedgehog signaling The dependence of Hh signaling on ciliary localization Mouse genetic data have provided compelling evidence leads to the question as to how the signal is transmitted that apart from their role as sensory organelles, cilia are from the cilium to the nucleus. In a surprising twist to the essential for Hedgehog (Hh) signal transduction. Mam- Hh story, Patched and Gli transcription factors were found malian Hh signaling is mediated by three Gli-Kruppel to localize in the cilium, and Smoothened was shown to transcription factor family members (Gli1–3). Without a move into the cilium in response to the Hh ligand, resulting Hh signal, Patched (the Hedgehog receptor) inhibits in processing of the Gli transcription factors within the Smoothened, and the Gli transcription factors are cleaved cilium. Consequently, defects in IFT, or other ciliary func- to repressor forms, whereas presence of a Hh signal tions, can lead to disruption of Hh signaling [13,16]. relieves this inhibition, resulting in full-length Gli proteins entering the nucleus and serving as transcrip- Glis factors: novel players in renal disease tional activators (reviewed in Refs. [12,13]). Evidence for a Further clues as to how signaling within and from the role of Sonic hedgehog (Shh) in kidney function has come primary cilium funnels into nuclear gene expression to from the analysis of human patients with renal malfor- maintain polarity of renal epithelial cells in the mature mations associated with Pallister-Hall syndrome kidney are now emerging. Recent evidence suggests that (Table 1), which is caused by mutations in the GLI3 gene. loss of function mutations in the murine zinc finger tran- These mutations are thought to result in a truncated GLI3 scription factor Gli-similar 2 (Glis2), as well as in human protein, and mice expressing only this shortened form GLIS2, lead to nephronophthisis [17,18]. Glis2 is one of have defective kidney development [12,14]. three Glis transcription factor family members whose zinc Mice with homozygous mutations for Shh or those fingers share high homology with the Gli family. Like the treated with cyclopamine (a Hedgehog antagonist), show Gli proteins, Glis2 is detected in the primary cilium, but it severe disruption of renal organogenesis, in the worst cases is not required for proper cilia formation. Interestingly, resulting in a complete lack of kidneys. In the absence of Glis2 seems to act as a transcriptional repressor by binding Hh signaling, reduced expression of Pax2, Sall1, cell cycle to Gli-consensus DNA binding sites and suppressing devel- regulators (CyclinD1 and N-Myc), Gli1 and Gli2 was opmental gene expression programs once kidney architec- observed. Intriguingly, Gli3 expression was increased in ture is established. Notably, all three Glis family members the absence of Shh, and deletion of Gli3 rescued the renal are expressed in overlapping patterns in the adult mouse phenotype of ShhÀ/À mice, restoring expression of Pax2, kidney. Furthermore, mutations in GLIS3 have been Sall1, CyclinD1, N-Myc, Gli1 and Gli2 [15]. These results shown to cause polycystic kidneys in humans [19] and together strongly suggest that these genes are direct tar- mice (Uhlenhaut and Treier, unpublished observations). gets of the Gli transcription factors, whereby Gli1 and 2 act Thus, Glis proteins in the adult kidney might be part of a as transcriptional activators and Gli3 predominantly func- transcriptional network downstream of cilia signaling tions as a transcriptional repressor in the absence of Shh. required for kidney integrity. It will be important to deter- Box 1. An overview of kidney development Mammalian kidney development proceeds through three successive until they finally connect with the collecting duct. This system of steps, termed the pronephros, the mesonephros and the metane- branching and differentiation is reiterated until nephrogenesis is phros. The pronephros is formed first and most rostrally (at E8.5 in completed shortly after birth in mice (reviewed in Refs. [74,75]). the mouse), followed by a more caudal formation of the mesonephros A mature nephron consists of highly specialized cell types carrying and finally the metanephros (at E10.5). The first two are transient out various physiological functions associated with waste excretion structures in mammals, and only the metanephros will become the from the blood. One end of the nephron is formed by the glomerulus, definite adult kidney [74,75] (see Figure I). followed by the proximal convoluted tubule, Henle’s loop and the Kidney development is characterized by sequential reciprocal distal convoluted tubule, which inserts into the collecting duct. The inductive interactions and mesenchymal-to-epithelial transforma- initial filtration of the blood occurs inside the glomerulus, where tions. It is initiated with the formation of the nephric ducts, or fenestrated endothelial capillary cells and glomerular podocytes Wolffian ducts (at E8 in the mouse), two epithelial tubes that originate create a filter (reviewed in Ref. [41]). This initial filtrate is concentrated from the intermediate mesoderm and extend toward the posterior of by selective reabsorption along the different segments of the renal the embryo. Metanephros development depends on interactions tubule. Glucose, amino acids, electrolytes and peptides are reab- between the metanephric mesenchyme (MM), a specialized group sorbed in the proximal convoluted tubule, whereas water and of kidney precursor cells, and the nephric duct. At the level of the electrolytes are taken up by Henle’s loop and the distal convoluted hindlimb bud, signaling from the MM induces evagination of the tubule, because of the segmental expression of distinct sets of solute ureteric bud (UB) from the nephric duct, which will invade the MM transporters [75]. Defects in the podocyte foot processes enveloping and form multiple branches. These branches will later form the the glomerular capillaries or in the basement membrane between the collecting duct system that funnels the urine into the bladder. At the two cell types usually lead to protein loss into the urine (proteinuria). tips of the branching ureter, the surrounding mesenchyme is induced Accordingly, malfunction of the above mentioned tubular segments to condense, epithelialize and differentiate into mature nephrons. The generally results in abnormally high levels of the corresponding differentiation of nephrons occurs through morphogenetic stages that molecules (e.g. glucose or electrolytes) within the urine, polyuria and are referred to as renal vesicles and comma- and S-shaped bodies dehydration. 3
  4. 4. TIGS-649; No of Pages 11 Review Trends in Genetics No.x Figure I. Schematic overview of mammalian kidney development and morphology. Kidney development proceeds through three stages: pronephros, mesonephros and metanephros. (a) The metanephros becomes the permanent kidney and is formed by invasion and branching of the ureteric bud from the nephric duct into the metanephric mesenchyme in a process of reciprocal inductive interactions. (b) The ureteric branches give rise to the collecting duct system and induce epithelialization of the surrounding mesenchyme, first creating renal vesicles and then comma- and S-shaped bodies and finally nephrons that join the collecting duct. (c) The nephron 4
  5. 5. TIGS-649; No of Pages 11 Review Trends in Genetics No.x Box 2. Transcription factors in early kidney development The transcriptional networks governing early kidney development have Gndf and Six2 [85], so these genes are all part of a common pathway been reviewed extensively elsewhere [4,74–76]. To summarize briefly, regulating early kidney development. Lineage specification events many of the early specification events center around the activation of require the establishment of gene expression patterns that is most glial cell line-derived neurotrophic factor (GDNF), a crucial signaling likely achieved through epigenetic modifications of local chromatin molecule that is secreted by the metanephric mesenchyme (MM) to structures. Pax2 has been reported to recruit the assembly of a histone induce budding and branching of the ureter. GDNF signals through its H3 lysine 4 methyltransferase complex through interaction with Pax receptor tyrosine kinase Ret and its coreceptor Gfra1, both of which are transcription activating domain interacting protein (PTIP) to activate expressed in the nephric duct [77]. target promoters [86], which might be a hint at a general mechanism of The evolutionarily conserved transcriptional hierarchy or circuitry of cell fate determination via this regulatory network. Eya/Pax/Six protein families are fundamental regulators of early kidney Apart from the regulation of Gdnf/Ret expression, other pathways development [78]. Mutations in human EYA1, SIX1 and SIX5 genes parallel to the aforementioned Eya1 and Pax2/8 are required for proper have been shown to underlie the branchial arch defects, hearing loss induction and specification of the metanephric field along the and renal anomalies associated with BOR (branchio-oto-renal) syn- rostrocaudal axis. Early kidney development also requires expression drome [78,79] (see Table 1). Pax2 and Pax8 cooperate in nephric lineage of Odd1 and Lim1 [74], two transcription factors expressed in the specification. Mice homozygous mutant for the Pax2 gene alone fail to intermediate mesoderm. Interestingly, the zinc-finger transcription induce the metanephric kidney, and Pax2/Pax8 double mutant mice fail factor Odd1 is downregulated on tubule differentiation, and persistent to form the pronephros. Likewise, in Eya1 homozygous mutant mice, expression of Odd1 in the chick prevents differentiation [87]. the metanephric mesenchyme fails to be specified, which results in Other genes required for renal branching morphogenesis include renal agenesis. Sall1 and Sall4, zinc finger proteins homologous to the Drosophila In the absence of the homeobox transcription factor Six1, which is gene spalt [88], the homeobox factor Emx2, which is required for expressed in the uninduced metanephric mesenchyme, ureteric bud ureteric bud functions after Pax2 [75], and WT1. WT1 mutations invasion is abolished, and the MM subsequently undergoes apoptosis underlie the urogenital malformations in WAGR, Denys-Drash, Frasier [80]. Similar to the observed synergy between Pax2 and Pax8, Six1/Six4 syndromes and Wilm’s tumor (reviewed in Ref. [43]). double mutants display a complete loss of a Pax2-expressing The reciprocal inductive interactions between the ureteric bud (UB) metanephric mesenchyme [81]. Six2 homozygous mutant mice have and the MM suggest the involvement of secreted signaling molecules a unique phenotype of kidney hypoplasia that is caused by early on top of GDNF. One important player that has surfaced in this process depletion of the mesenchymal precursor pool and premature differ- is the canonical Wnt pathway: Analysis of mutant mice has divulged entiation of the mesenchyme into nephrons, which also results in fewer that Wnt9b is a primary signal necessary for renal vesicle induction, ureteric branches [82]. including Wnt4 production [89]. Wnt4 itself seems to be an autocrine Not surprisingly, the Hox11 cluster, which is crucial for embryonic factor necessary for differentiation of the MM into epithelial nephrons. patterning along the anterioposterior axis at the level of the emerging In fact, Wnt4 was recently shown to be directly regulated by Pax2 kidney, is also required for renal development. Triple mutants for during renal vesicle formation [90]. Interestingly, subsequent renal Hoxa11/Hoxc11/Hoxd11 show a complete loss of metanephric kidney tubule differentiation is not compatible with activated, stabilized b- formation [83]. catenin, implying the need for a downregulation of Wnt signaling in Pax2, Six1, Six2 and Six4 have been implicated in regulating the later stages [32]. expression of Gdnf to stimulate ureteric bud outgrowth [77], whereas In conclusion, the specification along the anterioposterior and Gata3 has been suggested as a transcriptional regulator of Ret mediolateral axes to induce formation of MM and UB and to drive expression downstream of Pax2/8 in the developing nephric duct [84]. kidney morphogenesis requires the activation of multiple pathways. Interestingly, the Hox11 paralogous proteins have been shown to The relationship between these proteins and their interactions are form a complex with Pax2 and Eya1 to directly activate expression of complex and still incompletely understood. mine the peptide motifs and protein machinery that direct nucleus, where it activates activator protein 1 (AP-1)–de- Gli and Glis proteins to the cilia to fully understand the pendent transcriptional pathways [21,22]. Cell cycle regu- signal-dependent modifications of these proteins. lation via p21 induction can also occur by direct activation of JAK-STAT signaling by PKD1 and 2 [23]. In addition, Connecting the cilium with the nucleus processing of the C-terminal tail of PKD1 might be trig- Localization of transcriptional regulators to cilia and the gered in response to mechanosensation of fluid flow in cell membrane is not limited to the Gli and Glis families. renal tubules, resulting in ciliary-nuclear translocation Additional pathways allow the cilium to influence nuclear together with its interactors STAT6 and P100 [24]. gene transcription: the proteins encoded by PKD1 and Because no kidney malfunction has been reported in mice PKD2, polycystin-1 and polycystin-2, are transmembrane with mutated Id2 or Stat6 genes, the physiological import- glycoproteins that interact with one another and mediate a ance of these proteins in renal disease is not clear. Further- variety of complex formations. PKD2 binds to and seques- more, Pkd1-mutant mice show ectopic Pax2 expression, ters Id2, a basic helix–loop–helix (bHLH) transcription and deletion of Pax2 reduces cyst growth in Pkd1-deficient factor that regulates cell proliferation by suppressing mice, suggesting that PKD1 represses Pax2 in an, as yet, p21, a CDK inhibitor. By preventing nuclear localization unknown manner [25]. of Id2, PKD2 inhibits cell cycle progression by upregulating Similarly, polyductin (also known as fibrocystin) p21 [20]. Interestingly, this interaction requires the phos- encoded by PKHD1 is subject to proteolytic cleavage, which phorylation of polycystin-2. This phosphorylation reaction is in this case dependent on Ca2+- signaling [26]. Its large is dependent on PKD1, which can itself be proteolytically extracellular domain is shed from the cilium, whereas the cleaved, and its processed C-terminal tail can enter the intracellular part has been suggested to enter the nucleus represents the functional unit of the kidney and consists of a glomerulus, a proximal tubule, the loop of Henle and a distal tubule connected to the collecting duct. The initial blood filtration occurs inside the glomerulus, which harbors a dense capillary tuft, podocytes and supporting mesangial cells, surrounded by Bowman’s capsule. (d) Blood plasma passes through the fenestrated endothelium, the glomerular basement membrane, and ultimately through the slit diaphragm between interdigitating podocyte foot processes, which acts as a macromolecular filter, into the urinary space. 5
  6. 6. TIGS-649; No of Pages 11 Review Trends in Genetics No.x Figure 1. Schematic representation of a primary cilium. A primary cilium consists of a central axoneme made of microtubules enclosed by a distinct cell membrane. Several structural elements such as the periciliary membrane, the transition fibers and basal bodies form a selective barrier at the entrance of the cilium and create a unique environment that allows for compartmentalization. Protein products of genes implicated in polycystic kidney disease (‘cystic proteins’) localize to the basal body, membrane or axoneme of the cilium. Cilia are sensory organelles that can probe the extracellular environment, but they also act as signaling centers. Bending of the cilium by renal tubular flow causes an intracellular Ca2+ influx that sets off a variety of signaling cascades. Components of the Hedgehog (and other) signal transduction pathway(s) have been shown to depend on ciliary localization. The binding of the secreted Sonic hedgehog protein (Shh) to its receptor Patched, and the Smoothened- mediated processing of the Gli transcription factors has been detected in the cilium. The Gli transcription factors can move from there to the nucleus to regulate gene expression in response to Hedgehog signaling, either activating or repressing transcription (GliA or GliR). Other transcription factors, such as Stat6 and Glis2, and fragments of ‘cystic proteins’ have also been reported to localize to the cilium and the nucleus. after cleavage by gamma-secretase, in a manner analogous Maintenance of renal epithelial morphology to Notch processing [27]. Likewise, inversin, a protein In contrast to the putative physiological role of nuclear implicated in nephronophthisis, has been proposed to ciliary protein fragments, the function of b-catenin in localize to the nucleus [28,29]. Moreover, the ‘cystic transcriptional regulation downstream of canonical Wnt protein’ CEP290 binds to and modulates the activity of signaling is firmly established [31]. Canonical Wnt sig- the transcription factor ATF4 [30]. These results together naling is required during early kidney development, suggest that the cleaved fragments of various ciliary whereas the noncanonical planar cell polarity (PCP) path- proteins can have a co-activator/co-repressor-like role in way is required for the proper alignment of cell divisions transcriptional regulation. However, it is not yet clear if during epithelial tubule elongation [32–34]. Noncanonical these events occur in vivo and any functional consequences Wnt signaling is independent of b-catenin, but shares for kidney development and homeostasis remain to be several other pathway components such as Frizzled and elucidated. Dishevelled with the canonical Wnt signaling pathway. 6
  7. 7. TIGS-649; No of Pages 11 Review Trends in Genetics No.x Furthermore, it has been suggested that the ciliary protein but distinct functions in renal and gonadal development inversin triggers the switch between canonical and non- [43]. In particular, the absence of the +KTS form in Frasier canonical Wnt signaling, which could occur in response to syndrome causes defects in podocyte function [43]. At least urine flow [28,35]. In this respect, it is noteworthy that three ‘podocyte genes’ are regulated by WT1 directly: inversin interacts with b-catenin [28]. It is conceivable that podocalyxin, nephrin and Pax2. The relationship between adult kidney homeostasis requires a ‘shut-down’ of the Pax2 and WT1 is complex, and Pax2 expression in podo- canonical Wnt pathway after organogenesis is completed, cytes has been linked to repression of WT1. Interestingly, whereas the PCP pathway confers the necessary spatial ectopic Pax2 expression in glomerular podocytes has been information for appropriate mitotic spindle orientation in found in several pathological conditions. Persistent trans- renal tubules. Consequently, overexpression of a constitu- genic expression of Pax2, which is normally repressed tively active form of b-catenin in mice causes cystic renal during terminal differentiation of renal epithelial cells, disease [31]. Although there is evidence for disrupted has been shown to disrupt kidney function and morphology planar cell polarity in polycystic kidneys [33], a require- (cyst formation and absence of foot processes). These find- ment for ciliary localization has not been demonstrated for ings have been extended by another mouse model that components of the Wnt signaling pathway [11]. allows inducible expression of Pax2 in fully mature podo- We are beginning to gain a clearer insight into the cytes of adult kidneys, which leads to dedifferentiation and transcriptional regulation of the ‘cystic genes’ themselves, establishes a causal relationship between ectopic Pax2 in particular Pkd2 and Pkhd1. Recent evidence from mice activation and glomerular disease [44]. shows that the homeobox transcription factor hepatocyte The human nail-patella syndrome, which is often associ- nuclear factor-1b (Hnf1b), also known as transcription ated with renal disease, is caused by mutations in the LIM factor 2 (Tcf2), regulates Pkd2 (but not Pkd1) and Pkhd1 homeodomain transcription factor LMX1B [45]. LMX1B gene expression by binding directly to their promoters. has been shown to regulate the expression of a3(IV) and Consequently, deletion of HNF1b in murine kidneys leads a4(IV) collagen chains directly; these are essential com- to cyst formation and the downregulation of Pkd2, Pkhd1, ponents of the glomerular basement membrane and of Ift88 (also known as Tg737 or Polaris) and Umod; the latter podocin, a nephrin-binding membrane protein implicated two genes are involved in the development of renal cysts in steroid-resistant nephrotic syndrome [45]. A recent [36]. In humans, mutations in HNF1b cause the RCAD comprehensive study addressed the role of Lmx1b in glo- syndrome (renal cysts and diabetes) [37]. A similar phe- merular disease. Lmx1b-deficient podocytes fail to form notype was observed in mice with a targeted inactivation of foot processes and slit diaphragms, which leads to protei- the transcriptional coactivator Wwtr1/TAZ [38]. nuria. Moreover, podocyte-specific inactivation of Ldb1, In summary, the mechanisms controlling proliferation, which interacts with Lmx1b biochemically, also results differentiation and apoptosis of renal epithelial cells seem in a podocyte phenotype with gradual loss of foot processes to entail complex interactions between ciliary proteins and [46]. transcriptional regulators with cross-talk on multiple Furthermore, a subset of mutations in the forkhead levels. However, the functional significance this cross-talk transcription factor FOXC2 underlying the human lym- has for kidney physiology needs further analysis. phedema-distichiasis syndrome have been reported to be associated with renal malfunction [47]. Indeed, knockout Glomerular diseases: the podocyte takes center stage studies in mice have confirmed a role for Foxc2 in podocyte Glomerular diseases encompass a wide range of pathologi- development [47,48]. Promising candidate genes for unex- cally defined syndromes that account for most cases of plained forms of human inherited glomerular disease in- ESRD [39]. The glomerulus serves a primary function in clude MAFB, which encodes a basic domain leucine zipper filtering the urine from the blood, and failure in this transcription factor, and transcription factor 21 (TCF21) process might result in proteinuria and kidney failure also known as Podocyte-expressed 1 (POD1), which (see Figure I in Box 1). Common diseases, such as diabetes, encodes a bHLH transcription factor. Mouse models with hypertension, autoimmune diseases and toxic drug intake MafB or Tcf21/Pod1 gene disruptions affect podocyte func- can cause glomerular insults that mainly affect the podo- tion because of diminished expression of podocin and cyte, a highly specialized visceral epithelial cell type. nephrin [49–51]. Moreover, the Notch pathway has been Mutations in genes encoding structural components of shown to be essential for podocyte development [52]. The the podocyte foot processes, slit diaphragms or glomerular transcriptional regulator RBPjk, which can form hetero- basement membrane (such as nephrin, podocin, collagen dimeric complexes with other bHLH transcription factors, type IV and b2-laminin) have long been known to be causes functions downstream of Notch signaling. Interestingly, of glomerulopathies [40,41], but the transcriptional regu- genetic deletion of RBPjk in podocytes delays the pro- lation of these genes in renal physiology and disease is just gression of glomerular disease, providing another example beginning to become clear [42]. that termination of the developmental program is import- Wilms’ tumor protein 1 (WT1) is a zinc-finger transcrip- ant to prevent renal disease [53]. Additional candidate tion factor with several roles in kidney development and genes for the development of glomerular disease encode function [43]. The human Wilm’s tumor-aniridia-genitour- the zinc fingers and homeoboxes (ZHX) transcription fac- inary anomalies-mental retardation syndrome (WAGR) tors, which were reported to be expressed in podocytes and and the Denys-Drash and Frasier syndromes are all caused to regulate numerous functionally important podocyte by different mutations in WT1. The two main WT1 splice genes [42]. In the future, more genes will join the ranks isoforms referred to as ÀKTS and +KTS, have overlapping of regulators of podocyte function, as efforts are currently 7
  8. 8. TIGS-649; No of Pages 11 Review Trends in Genetics No.x being made to identify glomerulus-specific transcripts on a fibrosis [56,57]. Fibrosis is characterized by an excessive large scale [48]. Like all other renal epithelial cells, podo- accumulation and deposition of extracellular matrix cytes possess cilia. However the importance of cilia sig- (ECM) that progressively leads to the destruction of func- naling for podocyte function remains to be studied. tional nephrons. The majority of ECM is produced by As alluded to earlier, the most common cause of kidney a-smooth muscle actin expressing myofibroblasts [58]. failure is diabetic nephropathy. High glucose concen- Myofibroblasts are believed to form through phenotypic trations in the blood induce proliferation of another glo- transition of existing interstitial fibroblasts, mesangial merular cell type, the mesangial cell (see Figure I in Box 1). cells, or migration of more distant cells into the kidney Mesangial cell proliferation is a hallmark feature of glo- [59]. However, there is increasing evidence further sup- merulosclerosis, and has been correlated with production ported by the analysis of Glis2 mutant kidneys that myo- of angiotensin II, transforming growth factor b (TGF-b), fibroblasts can also originate from renal epithelial tubules and platelet-derived growth factors (PDGFs) [54]. In through epithelial-to-mesenchymal transition (EMT) particular, the JAK–STAT pathway mediates a significant [60,61] (Figure 2). Although EMT is an essential process part of the proliferative effects of PDGF and ANG II. JAK required for metazoan embryogenesis, it is responsible proteins are cytoplasmic tyrosine kinases, which once for the detrimental effects seen under pathophysiological activated phosphorylate STAT transcription factors, conditions of organ fibrosis and cancer metastasis [62,63]. resulting in their nuclear translocation and the activation Loss of Glis2 or other fibrotic responses induce expression of responsive promoters [54]. Furthermore, Y-Box protein of the zinc finger transcription factor Snail, which in turn 1, which has transcriptional regulatory activity, was impli- represses E-cadherin and Cadherin-16 expression. Down- cated as a mediator of PDGF-B–induced mesangial cell regulation of cadherin leads to a loss of cell adhesion and proliferation [55]. Inhibition of this pathway might thus cell polarity. Interestingly, Snail does not directly repress provide an interesting target for therapeutic intervention. Cadherin-16, but rather reduces expression of its activator HNF1b. Ectopic activation of Snail in adult mice has been Renal fibrosis: the final stage of chronic kidney disease shown to be sufficient to drive EMT and cause renal Regardless of the initial cause, virtually all types of fibrosis. Moreover, Snail upregulation can be observed chronic kidney disease are complicated by the histological in patients with fibrotic kidneys [64]. In addition, Gli1 appearance of glomerulosclerosis and tubulointerstitial was recently shown to regulate the expression of Snail, Figure 2. Signaling pathways in renal fibrosis. Renal epithelial tubules are formed by mesenchymal-to-epithelial transition (MET) from the metanephric mesenchyme during development, whereas the reverse process, epithelial-to-mesenchymal transition (EMT), is associated with the loss of cell polarity and adhesion leading to kidney fibrosis. During EMT, epithelial cells lose apical-basal characteristics and expression of cell adhesion molecules like E-cadherin, acquire mobility and adopt a fibroblast-like morphology. Factors such as TGFb, USAG-1, Snail, Gli1, KAP1 and CBF-A promote EMT and the appearance of myofibroblasts that are characterized by the expression of genes such as FSP1 and a-SMA (pink). In healthy renal tubules, proteins such as BMP7, KCP, Glis2 and HNF1b prevent fibrosis by stabilizing the expression of cadherins and the epithelial phenotype and inhibiting ectopic Gli1 or Snail activation (purple). 8
  9. 9. TIGS-649; No of Pages 11 Review Trends in Genetics No.x and Gli1-mediated Snail activation (followed by E-cad- technologies, will be useful to elucidate transcriptional herin downregulation) drives transformation of epithelial regulatory networks governing kidney physiology. In this cells in tumor progression [65]. These results emphasize respect, it is reassuring to see the publications of the first the requirement for repression of Gli-responsive promo- renal studies driven by a systems biology approach [72,73]. ters to prevent EMT. Fibroblasts created through EMT in Although we have learned much about early events the kidney express the FSP1 gene (known as S100a4 in the during metanephric development, there is still a lack of cancer literature), which encodes fibroblast-specific knowledge regarding later events such as patterning of protein 1. The transcriptional regulators, CArG box-bind- nephric tubule segments, and self-renewal of the mesench- ing factor-A (CBF-A) and KRAB-associated protein 1 ymal progenitor pool. Furthermore, it is becoming increas- (KAP-1) bind to distinct DNA motifs in the promoter of ingly clear that ‘terminally’ differentiated cell types in the FSP1 and activate its transcription. Similar binding mature kidney might not exist. This is best underscored by sites can be found in the promoters of several other recent observations of the reactivation of developmental EMT-associated transcripts such as Twist, Snail, E-cad- transcription factors in renal disease progression, as herin, vimentin, a1(I)collagen and a-smooth muscle actin, shown for Pax2 and RBPjk in polycystic kidney and glo- all of which are activated by the CBF-A/KAP-1 complex merular disease and for Gli1 and Snail in renal fibrosis. [66,67] (Figure 2). Thus, adult kidney homeostasis seems to rely on active Our understanding of the transcriptional network con- silencing of developmental gene expression programs, as trolling EMT in different organ systems is improving fast. It exemplified by the analysis of Glis2 function. The under- is generally thought that TGF-b and its downstream SMAD appreciated cellular plasticity in the kidney, however, signaling play an essential role in most forms of chronic might open up untapped sources for the treatment of kidney disease. Expression of TGF-b in transgenic mice chronic kidney disease. promotes EMT and fibrosis, whereas inhibition of TGF-b In this respect, it will be of tremendous interest to eluci- by different approaches (including overexpression of the date the molecular mechanisms of cilia signaling beyond its inhibitory Smad7) prevents it [60,68]. Another member of proposed function as a mechanosensor of renal tubular flow. the TGF-b superfamily, BMP7, which is required for early Furthermore, studying the regulation and necessity of cili- kidney development, has the opposite effect: it counteracts ary localization for various signaling pathways and its func- EMT and prevents fibrosis [68,69]. Furthermore, modifiers tional importance in kidney development and disease has of BMP signaling, such as the enhancer KCP and the BMP already begun to open up a new field of investigation. For antagonist USAG-1, have been shown to improve or worsen most transcription factors that are important during early the formation of fibrous tissue, respectively [69,70]. kidney organ induction and patterning, their role during Thus, molecular mechanisms underlying kidney fibrosis later morphogenetic stages is still not clarified. Thus, it suggest that renal fibrosis can be thought of as reversal of will be important to systematically take advantage of early kidney development. However, we have much to conditionally and temporally controlled gene disruption learn about the transcriptional network that drives the approaches in mice to illuminate their specific function in formation of renal epithelial cells through mesenchymal- mature nephrons and during kidney disease. Finally, con- to-epithelial transition (MET) during development. This ditional mutagenesis and genetic screens in human patients, information will be useful in designing novel therapeutic zebrafish or other model organisms will continue to yield strategies to reverse kidney fibrosis (Figure 2). novel genes required for kidney organ development. Clearly a lot still needs to be learned about organ de- Concluding remarks and open questions velopment and physiology in this fascinating model system Transcription factors not only serve as genetic markers for to open new avenues for therapeutic interventions in the specific cell populations but more importantly orchestrate battle against the increasing pandemic of chronic kidney the genetic program within each cell. Therefore, they disease (Box 3). provide useful entry points to decipher the cis-regulatory networks that underlie the coordinated expression of specific sets of genes to create the various renal cell types Box 3. Outstanding questions and future directions required for kidney function. What are the gene expression signatures of the specialized renal cell Over recent years, many transcriptional regulators of types in the adult kidney, and what is their relationship to renal kidney development have been identified, but most of the physiology and tissue homeostasis? target genes controlled by these transcription factors What is the lineage relationship of the differentiated renal cell types and what is the extent of renal cellular plasticity in the adult organ? remain elusive (with few exceptions). Likewise, the hier- What can be learned from the identification of the transcriptional archical relationships between the individual regulators networks downstream of cilia signaling in the adult kidney? are thus far difficult to assess. In the future, it will be Why is only part of the developmental program reactivated in renal important to move beyond descriptive approaches of loss- injury and repair and how do these processes differ from renal fibrosis? of-function phenotypes for single genes. Time courses and What are the pathways that terminate mesenchymal-to-epithelial high-throughput validation of the expression profiles transition during renal development and is epithelial-to mesench- obtained from loss-of-function studies should help to ymal transition in kidney fibrosis reversible? identify gene expression signatures that are important Do true adult renal stem cells exist which could be utilized for renal for kidney development and disease [48,71,72]. In vivo replacement and repair therapy after injury? What are the renal disease-associated transcriptional programs chromatin immunoprecipitation (ChIP) studies, in combi- resulting from ageing, diabetes, obesity and hypertension? nation with genomics, bioinformatics and proteomics 9
  10. 10. TIGS-649; No of Pages 11 Review Trends in Genetics No.x Acknowledgements 27 Kaimori, J.Y. et al. (2007) Polyductin undergoes notch-like processing The authors apologize to all colleagues whose excellent work could not be and regulated release from primary cilia. Hum. Mol. Genet. 16, 942– cited because of space constraints. The authors thank Petra Riedinger for 956 help with figures. 28 Nurnberger, J. et al. (2002) Inversin forms a complex with catenins and N-cadherin in polarized epithelial cells. Mol. Biol. Cell 13, 3096–3106 References 29 Otto, E.A. et al. (2003) Mutations in INVS encoding inversin cause 1 Weening, J.J. (2004) Advancing nephrology around the globe: an nephronophthisis type 2, linking renal cystic disease to the function of invitation to contribute. J. Am. Soc. Nephrol. 15, 2761–2762 primary cilia and left-right axis determination. Nat. Genet. 34, 413–420 2 Hallan, S.I. et al. (2006) International comparison of the relationship of 30 Sayer, J.A. et al. (2006) The centrosomal protein nephrocystin-6 is chronic kidney disease prevalence and ESRD risk. J. Am. Soc. Nephrol. mutated in Joubert syndrome and activates transcription factor ATF4. 17, 2275–2284 Nat. Genet. 38, 674–681 3 Chatziantoniou, C. and Dussaule, J.C. (2008) Is kidney injury a 31 Benzing, T. et al. (2007) Wnt signaling in polycystic kidney disease. J. reversible process? Curr. Opin. Nephrol. Hypertens. 17, 76–81 Am. Soc. Nephrol. 18, 1389–1398 4 Schedl, A. (2007) Renal abnormalities and their developmental origin. 32 Park, J.S. et al. (2007) Wnt/beta-catenin signaling regulates nephron Nat. Rev. Genet. 8, 791–802 induction during mouse kidney development. Development 134, 2533– 5 Bisgrove, B.W. and Yost, H.J. (2006) The roles of cilia in developmental 2539 disorders and disease. Development 133, 4131–4143 33 Fischer, E. et al. (2006) Defective planar cell polarity in polycystic 6 Hildebrandt, F. and Otto, E. (2005) Cilia and centrosomes: a unifying kidney disease. Nat. Genet. 38, 21–23 pathogenic concept for cystic kidney disease? Nat. Rev. Genet. 6, 928– 34 Schmidt-Ott, K.M. et al. (2007) beta-catenin/TCF/Lef controls a 940 differentiation-associated transcriptional program in renal epithelial 7 Satir, P. and Christensen, S.T. (2007) Overview of structure and progenitors. Development 134, 3177–3190 function of mammalian cilia. Annu. Rev. Physiol. 69, 377–400 35 Simons, M. et al. (2005) Inversin, the gene product mutated in 8 Reiter, J.F. and Mostov, K. (2006) Vesicle transport, cilium formation, nephronophthisis type II, functions as a molecular switch between and membrane specialization: the origins of a sensory organelle. Proc. Wnt signaling pathways. Nat. Genet. 37, 537–543 Natl. Acad. Sci. U. S. A. 103, 18383–18384 36 Gresh, L. et al. (2004) A transcriptional network in polycystic kidney 9 Davenport, J.R. et al. (2007) Disruption of intraflagellar transport in disease. EMBO J. 23, 1657–1668 adult mice leads to obesity and slow-onset cystic kidney disease. Curr. 37 Igarashi, P. et al. (2005) Roles of HNF-1beta in kidney development Biol. 17, 1586–1594 and congenital cystic diseases. Kidney Int. 68, 1944–1947 10 Piontek, K. et al. (2007) A critical developmental switch defines the 38 Hossain, Z. et al. (2007) Glomerulocystic kidney disease in mice with a kinetics of kidney cyst formation after loss of Pkd1. Nat. Med. 13, 1490– targeted inactivation of Wwtr1. Proc. Natl. Acad. Sci. U. S. A. 104, 1495 1631–1636 11 Hildebrandt, F. and Zhou, W. (2007) Nephronophthisis-associated 39 Wiggins, R.C. (2007) The spectrum of podocytopathies: a unifying view ciliopathies. J. Am. Soc. Nephrol. 18, 1855–1871 of glomerular diseases. Kidney Int. 71, 1205–1214 12 Gill, P.S. and Rosenblum, N.D. (2006) Control of murine kidney 40 Michaud, J.L. and Kennedy, C.R. (2007) The podocyte in health and development by sonic hedgehog and its GLI effectors. Cell Cycle 5, disease: insights from the mouse. Clin. Sci. (Lond.) 112, 325–335 1426–1430 41 Quaggin, S.E. and Kreidberg, J.A. (2008) Development of the renal 13 Eggenschwiler, J.T. and Anderson, K.V. (2007) Cilia and developmental glomerulus: good neighbors and good fences. Development 135, 609–620 signaling. Annu. Rev. Cell Dev. Biol. 23, 345–373 42 Chugh, S.S. (2007) Transcriptional regulation of podocyte disease. 14 Bose, J. et al. (2002) Pallister-Hall syndrome phenotype in mice mutant Transl. Res. 149, 237–242 for Gli3. Hum. Mol. Genet. 11, 1129–1135 43 Rivera, M.N. and Haber, D.A. (2005) Wilms’ tumour: connecting 15 Hu, M.C. et al. (2006) GLI3-dependent transcriptional repression of tumorigenesis and organ development in the kidney. Nat. Rev. Gli1, Gli2 and kidney patterning genes disrupts renal morphogenesis. Cancer 5, 699–712 Development 133, 569–578 44 Wagner, K.D. et al. (2006) An inducible mouse model for PAX2- 16 Rohatgi, R. et al. (2007) Patched1 regulates hedgehog signaling at the dependent glomerular disease: insights into a complex pathogenesis. primary cilium. Science 317, 372–376 Curr. Biol. 16, 793–800 17 Attanasio, M. et al. (2007) Loss of GLIS2 causes nephronophthisis in 45 Morello, R. et al. (2001) Regulation of glomerular basement membrane humans and mice by increased apoptosis and fibrosis. Nat. Genet. 39, collagen expression by LMX1B contributes to renal disease in nail 1018–1024 patella syndrome. Nat. Genet. 27, 205–208 18 Kim, Y.S. et al. (2008) Kruppel-like zinc finger protein glis2 is essential 46 Suleiman, H. et al. (2007) The podocyte-specific inactivation of Lmx1b, for the maintenance of normal renal functions. Mol. Cell. Biol. 28, Ldb1 and E2a yields new insight into a transcriptional network in 2358–2367 podocytes. Dev. Biol. 304, 701–712 19 Senee, V. et al. (2006) Mutations in GLIS3 are responsible for a 47 Yildirim-Toruner, C. et al. (2004) A novel frameshift mutation of rare syndrome with neonatal diabetes mellitus and congenital FOXC2 gene in a family with hereditary lymphedema-distichiasis hypothyroidism. Nat. Genet. 38, 682–687 syndrome associated with renal disease and diabetes mellitus. Am. 20 Li, X. et al. (2005) Polycystin-1 and polycystin-2 regulate the cell cycle J. Med. Genet. A. 131, 281–286 through the helix-loop-helix inhibitor Id2. Nat. Cell Biol. 7, 1202–1212 48 Takemoto, M. et al. (2006) Large-scale identification of genes 21 Chauvet, V. et al. (2004) Mechanical stimuli induce cleavage and implicated in kidney glomerulus development and function. EMBO nuclear translocation of the polycystin-1 C terminus. J. Clin. Invest. J. 25, 1160–1174 114, 1433–1443 49 Moriguchi, T. et al. (2006) MafB is essential for renal development and 22 Guay-Woodford, L.M. (2004) RIP-ed and ready to dance: new F4/80 expression in macrophages. Mol. Cell. Biol. 26, 5715–5727 mechanisms for polycystin-1 signaling. J. Clin. Invest. 114, 1404–1406 50 Sadl, V. et al. (2002) The mouse Kreisler (Krml1/MafB) segmentation 23 Bhunia, A.K. et al. (2002) PKD1 induces p21(waf1) and regulation of gene is required for differentiation of glomerular visceral epithelial the cell cycle via direct activation of the JAK-STAT signaling pathway cells. Dev. Biol. 249, 16–29 in a process requiring PKD2. Cell 109, 157–168 51 Quaggin, S.E. et al. (1999) The basic-helix-loop-helix protein pod1 is 24 Low, S.H. et al. (2006) Polycystin-1, STAT6, and P100 function in a critically important for kidney and lung organogenesis. Development pathway that transduces ciliary mechanosensation and is activated in 126, 5771–5783 polycystic kidney disease. Dev. Cell 10, 57–69 52 Cheng, H.T. et al. (2007) Notch2, but not Notch1, is required for 25 Stayner, C. et al. (2006) Pax2 gene dosage influences cystogenesis in proximal fate acquisition in the mammalian nephron. Development autosomal dominant polycystic kidney disease. Hum. Mol. Genet. 15, 134, 801–811 3520–3528 53 Niranjan, T. et al. (2008) The Notch pathway in podocytes plays a role 26 Hiesberger, T. et al. (2006) Proteolytic cleavage and nuclear in the development of glomerular disease. Nat. Med. 14, 290–298 translocation of fibrocystin is regulated by intracellular Ca2+ and 54 Marrero, M.B. et al. (2006) Role of the JAK/STAT signaling pathway activation of protein kinase C. J. Biol. Chem. 281, 34357–34364 in diabetic nephropathy. Am. J. Physiol. Renal Physiol. 290, F762–F768 10
  11. 11. TIGS-649; No of Pages 11 Review Trends in Genetics No.x 55 van Roeyen, C.R. et al. (2005) Y-box protein 1 mediates PDGF-B effects 75 Bouchard, M. (2004) Transcriptional control of kidney development. in mesangioproliferative glomerular disease. J. Am. Soc. Nephrol. 16, Differentiation 72, 295–306 2985–2996 76 Dressler, G.R. (2006) The cellular basis of kidney development. Annu. 56 Fogo, A.B. (2007) Mechanisms of progression of chronic kidney disease. Rev. Cell Dev. Biol. 22, 509–529 Pediatr. Nephrol. 22, 2011–2022 77 Costantini, F. and Shakya, R. (2006) GDNF/Ret signaling and the 57 Khwaja, A. et al. (2007) The management of CKD: a look into the development of the kidney. Bioessays 28, 117–127 future. Kidney Int. 72, 1316–1323 78 Brodbeck, S. and Englert, C. (2004) Genetic determination of 58 Simonson, M.S. (2007) Phenotypic transitions and fibrosis in diabetic nephrogenesis: the Pax/Eya/Six gene network. Pediatr. Nephrol. 19, nephropathy. Kidney Int. 71, 846–854 249–255 59 Wada, T. et al. (2007) Fibrocytes: a new insight into kidney fibrosis. 79 Hoskins, B.E. et al. (2007) Transcription factor SIX5 is mutated in Kidney Int. 72, 269–273 patients with branchio-oto-renal syndrome. Am. J. Hum. Genet. 80, 60 Liu, Y. (2006) Renal fibrosis: new insights into the pathogenesis and 800–804 therapeutics. Kidney Int. 69, 213–217 80 Xu, P.X. et al. (2003) Six1 is required for the early organogenesis of 61 Kalluri, R. and Neilson, E.G. (2003) Epithelial-mesenchymal transition mammalian kidney. Development 130, 3085–3094 and its implications for fibrosis. J. Clin. Invest. 112, 1776–1784 81 Kobayashi, H. et al. (2007) Six1 and Six4 are essential for Gdnf 62 Shook, D. and Keller, R. (2003) Mechanisms, mechanics and function of expression in the metanephric mesenchyme and ureteric bud epithelial-mesenchymal transitions in early development. Mech. Dev. formation, while Six1 deficiency alone causes mesonephric-tubule 120, 1351–1383 defects. Mech. Dev. 124, 290–303 63 Radisky, D.C. et al. (2007) Fibrosis and cancer: do myofibroblasts 82 Self, M. et al. (2006) Six2 is required for suppression of nephrogenesis come also from epithelial cells via EMT? J. Cell. Biochem. 101, 830–839 and progenitor renewal in the developing kidney. EMBO J. 25, 5214– 64 Boutet, A. et al. (2006) Snail activation disrupts tissue homeostasis and 5228 induces fibrosis in the adult kidney. EMBO J. 25, 5603–5613 83 Wellik, D.M. et al. (2002) Hox11 paralogous genes are essential for 65 Li, X. et al. (2007) Gli1 acts through Snail and E-cadherin to promote metanephric kidney induction. Genes Dev. 16, 1423–1432 nuclear signaling by beta-catenin. Oncogene 26, 4489–4498 84 Grote, D. et al. (2006) Pax 2/8-regulated Gata 3 expression is necessary 66 Venkov, C.D. et al. (2007) A proximal activator of transcription in for morphogenesis and guidance of the nephric duct in the developing epithelial-mesenchymal transition. J. Clin. Invest. 117, 482–491 kidney. Development 133, 53–61 67 Teng, Y. et al. (2007) Transcriptional regulation of epithelial- 85 Gong, K.Q. et al. (2007) A Hox-Eya-Pax complex regulates early kidney mesenchymal transition. J. Clin. Invest. 117, 304–306 developmental gene expression. Mol. Cell. Biol. 27, 7661–7668 68 Wang, W. et al. (2005) Transforming growth factor-beta and Smad 86 Patel, S.R. et al. (2007) The BRCT-domain containing protein PTIP signalling in kidney diseases. Nephrology (Carlton) 10, 48–56 links PAX2 to a histone H3, lysine 4 methyltransferase complex. Dev. 69 Yanagita, M. (2006) Modulator of bone morphogenetic protein Cell 13, 580–592 activity in the progression of kidney diseases. Kidney Int. 70, 989–993 87 James, R.G. et al. (2006) Odd-skipped related 1 is required for 70 Lin, J. et al. (2005) Kielin/chordin-like protein, a novel enhancer of BMP development of the metanephric kidney and regulates formation signaling, attenuates renal fibrotic disease. Nat. Med. 11, 387–393 and differentiation of kidney precursor cells. Development 133, 71 Schwab, K. et al. (2006) Comprehensive microarray analysis of Hoxa11/ 2995–3004 Hoxd11 mutant kidney development. Dev. Biol. 293, 540–554 88 Nishinakamura, R. and Osafune, K. (2006) Essential roles of Sall 72 McMahon, A.P. et al. (2008) GUDMAP: the genitourinary developmental family genes in kidney development. J. Physiol. Sci. 56, 131–136 molecular anatomy project. J. Am. Soc. Nephrol. 19, 667–671 89 Carroll, T.J. et al. (2005) Wnt9b plays a central role in the regulation of 73 He, L. et al. (2008) The glomerular transcriptome and a predicted mesenchymal to epithelial transitions underlying organogenesis of the protein-protein interaction network. J. Am. Soc. Nephrol. 19, 260–268 mammalian urogenital system. Dev. Cell 9, 283–292 74 Boyle, S. and de Caestecker, M. (2006) Role of transcriptional networks 90 Torban, E. et al. (2006) PAX2 activates WNT4 expression in coordinating early events during kidney development. Am. J. during mammalian kidney development. J. Biol. Chem. 281, 12705– Physiol. Renal Physiol. 291, F1–F8 12712 11