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Home , Body cavity, Kidney development, Organ (biology), Ureteric bud

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Cell of Development

† Adrian S. Woolf* and Jamie A. Davies

*School of Biomedicine, University of Manchester, Manchester Academic Health Science Centre and Manchester Children’s Hospital, Manchester, United Kingdom; and †Centre for Integrative , Hugh Robson Building, University of Edinburgh, Edinburgh, United Kingdom

ABSTRACT The mammalian ureter contains two main types: a multilayered water-tight ep- The nephric (or Wolffian) ducts (NDs) ithelium called the urothelium, surrounded by layers that, by gen- are a pair of epithelial tubes, each of which erating proximal to distal peristaltic waves, pump from the renal toward runs along the edge of the intermediate the . Here, we review the cellular mechanisms involved in the de- near the . Each velopment of these tissues, and the molecules that control the process. We consider ND gives rise to a ureteric precursor, the the relevance of these biologic findings for understanding the pathogenesis of (UB), which grows into human ureter malformations. metanephric mesenchymal (MM) cells condensing out of intermediate meso- J Am Soc Nephrol 24: 19–25, 2013. doi: 10.1681/ASN.2012020127 derm. Normally, a single bud emerges from each ND near its distal (caudal) Molecule Abbreviation Box end, a precision facilitating optimal ALK Activin receptor-like kinase (growth factor receptor) interaction between the UB and MM, AngII Angiotensin II (growth factor) which are required to generate a single BMP morphogenetic protein (growth factor) ureter- functional unit of normal DLGH Discs-large homolog (intracellular scaffolding protein) 1–3 ERK Extracellular signal-regulated kinase (intracellular signaling molecule) shape and internal . ETV ETS transcription factor (transcription factor) In principle, normal budding could be FGFR Fibroblast growth factor receptor (growth factor receptor) controlled either by prepatterning within FOX Forkhead box (transcription factor) the itself or by external signals. FRAS Fraser syndrome (basement membrane molecule) FREM FRAS1-related (basement membrane molecule) Experiments with explanted NDs provide GDNF Glial cell line-derived neurotrophic factor (growth factor) no evidence for a strong intrinsic pre- GATA GATA-binding factor (transcription factor) pattern. Instead, any part of the duct, even GFR GDNF family receptor (growth factor receptor) the more proximal (cranial) section lying HCN3 Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 (ion channel) alongside the mesonephric kidney, can HNF1B Hepatocyte nuclear factor 1B (transcription factor) be stimulated to emit ectopic UBs by KIT v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (growth factor applying select molecules,4–8 the actions receptor) of which are understood by considering MYOCD Myocardin (transcription factor associated protein) PAX Paired box (transcription factor) intracellular pathways under their con- PI3K Phosphatidylinositol 3-kinase (intracellular signaling molecule) trol7 (Figure 1). PLC Phospholipase C (intracellular signaling molecule) PTCH Patched (growth factor receptor) RET Rearranged during transfection (growth factor receptor) Published online ahead of print. Publication date ROBO Roundabout (growth factor receptor) available at www.jasn.org. ROCK Rho-associated protein kinase (intracellular signaling molecule) Correspondence: Dr.AdrianS.Woolf,Schoolof SMAD Homologs of Drosophila protein, mothers against decapentaplegic and Biomedicine, University of Manchester, Manchester protein SMA (intracellular signaling molecule) Academic Health Science Centre and Manchester SHH Sonic hedgehog (growth factor) Children’s Hospital, Michael Smith Building, Ox- SLIT Slit homolog (growth factor) ford Road, Manchester, M13 9PT, UK, or Dr. Jamie SOX SRY-related HMG-box (transcription factor) A. Davies, Centre for Integrative Physiology, Hugh TBX T-box (transcription factor) Robson Building, 15 George Square, Edinburgh TGF Transforming growth factor (growth factor) EH8 9XD, UK. Email: [email protected]. TSHZ Teashirt (transcription factor) uk or [email protected] UPK Uroplakin (urothelial membrane protein) VANGL Van Gogh-like (planar cell polarity protein) Copyright © 2013 by the American Society of Nephrology

J Am Soc Nephrol 24: 19–25, 2013 ISSN : 1046-6673/2401-19 19 BRIEF REVIEW www.jasn.org

UB emergence is antagonized by AngII-mediated Sprouty-1 (SPRY1) greatest ERK/PI3K/PLC activation SMAD signaling but favored by ERK, downregulation,19,20 favor formation of move together and produce the bud.24 PI3K, and PLC activation. NDs express a solitary, correctly placed UB (Figure 2). This movement is also modulated by activin A, which acts in an autocrine An autocrine loop involving neuropep- ETV4 and ETV5, transcription factors manner to activate SMADs and prevent tide Y may enhance the commitment of upregulated by GDNF/RET signaling.24 budding. However, when an isolated ND these ND cells to budding.21 During UB branching, epithelial cells is treated with both an activin antagonist ND budding is preceded by increased become wedge shaped, implicating cyto- and a growth factor that activates ERK, epithelial proliferation22 and thicken- skeletal changes involving actin micro- PI3K, and PLC pathways, multiple buds ing to a pseudostratified .23 filaments. Indeed, of genes emerge along its length. In such experi- RET signaling leads to rearrangement encoding for the actin depolymerizing ments, numerous normal diameter buds of ND cells such that those with the factors, cofilin 1 and destrin, affect rather than one large cyst are generated, implying a yet-to-be-defined lateral in- hibition mechanism whereby bud tip cells direct their immediate neighbors to remain quiescent. ND cells express various cell surface receptors, each of which binds pro- branching or antibranching factors. RET and FGFR2 receptor tyrosine ki- nases, and their GFRa and sulfated gly- cosaminoglycan coreceptors, bind GDNF and FGFs, activating ERK, PI3K, and PLC pathways driving UB emergence.9,10 Expression of such re- ceptors depends on duct cells express- ing the GATA3 transcription factor,11 and b-catenin, a multifunctional intra- cellular protein,12,13 and on nearby Figure 1. Intracellular pathways modulating UB emergence from the ND. Pathways that stromal cells synthesizing retinoic acid, encourage (green) and pathways that inhibit (red) bud emergence are depicted. (See also the Molecule Abbreviation Box.) an effector metabolite of vitamin A.14 The extent of intracellular signaling triggered by receptor tyrosine kinases is limited by the cytoplasmic protein sprouty-1, without which the ND pro- duces multiple ectopic buds.15 In addi- tion, signaling between SLIT2 and ROBO2,16 members of molecular fam- ilies first implicated in neural guidance, together with expression of FOXC1 transcription factor,2 guard against UB ectopia by limiting the cranial extent of the GDNF expression domain within . As alluded to above, bud emergence is also antagonized by TGFb family mem- bers (activins and BMPs), autocrine and paracrine factors that bind ALK receptor threonine kinases, activating the SMAD Figure2. GrowthfactorscontrollingUBemergencefromtheND.Thecaudalpartoftheembryo, pathway.17 Normally, in vivo,SMADac- with the /urogenital , is on the left of the diagram. Except near the MM, inhibitory tivation is favored along most of the signals such as BMP4 and activin dominate the molecular landscape. MM produces activators 18 ’ ND. By contrast, near the duct scaudal such as GDNF in addition to GREM1 and follistatin, which respectively antagonize the anti- end, MM secretes the BMP antagonist, branching factors BMP4 and activin. At this precise point, the balance between activation and Gremlin-1 (GREM1),17 and the RET inhibition favors emergence of a single UB. (See also the Molecule Abbreviation Box.) Note that agonist,GDNF;these,togetherwith are not formed by ND branching but arise from adjacent .

20 Journal of the American Society of Nephrology J Am Soc Nephrol 24: 19–25, 2013 www.jasn.org BRIEF REVIEW branching,25 as does inhibition of signals from the forming bladder.36 urine is not needed for longitudinal ROCK, a molecule driving actin rear- Thevesicouretericjunctionthenbe- growth, although these experiments do rangements.26,27 ROCK is itself modu- comes physically separated from the not rule out a more subtle, differentiation- lated by the planar cell polarity protein, opening of the ND, maintained in males optimizing influence conferred by urine VANGL2. 28 In vitro, UB epithelia undergo as the ejaculatory duct, as they are flow that, in mice, probably begins sev- apoptotic death if physically separated pushed apart by growth of the bladder eral days after UB initiation when the from MM, and mesenchymal-derived wall. metanephros has formed its first layers factors such as GDNF may facilitate UB of vascularized glomeruli (Figure 3). survival as well as emergence.29 The PAX2 Urothelia in both the ureter and blad- transcription factor is normally expressed FURTHER GROWTH der have evolved to stop movement of in the ND and the emerging bud and is AND DIFFERENTIATION urine back into the body. Prevention of antiapoptotic in the UB/collecting duct OF URETERIC EPITHELIA movement of water and solutes through lineage.30,31 Prominent ND/UB apoptosis the apical-most epithelial layer is medi- and impaired UB formation occurs in The shaft of the UB, between the kidney ated by plaques made of UPK protein embryos lacking HNF1B (also known as and the ND, grows and differentiates to heterodimers.45,46 UPK expression occurs vHNF).32 This transcription factor is nor- become the mature ureter. In contrast to early in urinary tract development, being mally expressed in the ND/UB, where it UB initiation, less is known about the present in epithelia lining the urogenital may directly upregulate PAX2.32 of ureteric growth. Once sinus.47,48 In mutant mice lacking either emerged, the bud runs straight to the UPK3A or UPK2 proteins, plaques are MM but the guidance mechanisms are disorganized and urothelia are leaky. WHAT HAPPENS TO THE TOP not understood. When extra UBs are These also have malformed uri- AND BOTTOM OF THE BUD? induced with beads soaked in stimula- nary tracts with gaping (instead of normal tory growth factors, they do not always slit-like) vesicoureteric junctions, and di- Once the UB enters the MM, it begins to grow toward the beads,5 arguing against lated associated with either reflux branch to produce kidney collecting ducts. simple chemotaxis. Initial extension of of urine from the bladder or occlusion by Consideration ofthese events is beyond the the emerging UB depends on its epithe- exuberant urothelial growth.49,50 These remit of this review and has been covered lia expressing FRAS1.37 This basement structural anomalies might simply be sec- elsewhere.7,13 It is unclear how similar the membrane protein acts in a complex ondary disruptions following on from loss mechanisms of UB emergence are to its with two related molecules, FREM1 of the urothelial physical barrier. It has, subsequent arborization. Interestingly, and FREM2, probably optimizing pre- however, been postulated45 that they the proximal-distal axis of the UB does sentation of MM-derived growth factors may also result from perturbed intracellu- not initially restrict the branching ability to the bud38 and also physically stabi- lar signaling by analogy with the proven of its cells because, experimentally, a col- lizing UB/MM interactions by binding role for uroplakin proteins in trigger- lecting duct tree can be generated from integrin a8.39 A similar lack of UB pro- ing embryogenesis in frog eggs. UPK ex- either end of the nascent ureter.33 gression occurs in mutant mice lacking pression is compromised in ureters of The just-formed ureter is separated this matrix receptor, which is normally mouse embryos engineered to have from the , the bladder expressed on the surfaces of MM cells.40 precursor, by a length of ND extending As it extends, the bud becomes thin- beyond the point of UB emergence.34 ner than the zone of ND that produced When development is complete, how- it, suggesting cell rearrangements involv- ever, the ureter connects directly to the ing convergent extension, which is bladder, an anatomic change requiring known to drive the remarkable longitu- substantial remodeling. Previous teach- dinal growth of Malpighian kidney tu- ing postulated that the caudal-most ND bules in flyembryos.41 Ureters are cells migrated into the base of the blad- shorter than normal in TBX18 null mu- der, where they formed the urothelium tant mice.42 This transcription factor is of the trigone, the triangular zone be- normally expressed in mesenchymal cells tween the ureteric orifices and the ure- surrounding the urothelial stalk and its ab- thral outlet of the bladder; as this occurs, sence is associated with decreased epithe- the ureter/ND junction would approxi- lial proliferation.42 Once initiated, further mate to the bladder wall. Lineage tracing longitudinal growth occurs in isolated of genetically labeled ND cells shows that wild-type embryonic ureters maintained the first part of this model is incorrect.35 in culture43 and in ureters of certain In fact, the caudal-most part of the ND mutant embryos lacking kidneys.44 Both Figure 3. Harmonized functional devel- involutes by apoptosis induced by observations show that exposure to fetal opment of the kidney and ureter.

J Am Soc Nephrol 24: 19–25, 2013 Ureter Development 21 BRIEF REVIEW www.jasn.org downregulated BMP451 or TBX18,42 both stromal cells between the urothelium and severe, and rarest (about 0.01%–0.1% proteins being normally expressed in ad- SM layer is perturbed, suggesting that births), is its unilateral or bilateral ab- jacent SM precursor cells. Furthermore, may somehow control SM bundle sence, characteristically accompanied application of BMP4 to explanted meta- alignment. Cell lineage experiments by kidney agenesis.66 Ureteric dilation nephroi induces UPK expression in ure- shown that ureteric SM is distinct from associated with ureteropelvic junction teric bud branch tips within the organ,51 muscle layers in the wall of the urinary obstruction or primary megaureter af- suggesting that these UB descendants can bladder.57 After the shaft of the ureter fects up to 0.2% births (reviewed by be reprogrammed into a urothelial fate. has become enveloped with SM, there Lye et al.52). Even more common is ure- appears to be a secondary wave of muscle teric duplication (2% of the ); differentiation at the proximal end (top) in its most severe form the kidney is also URETERIC MUSCLE FORMATION of the ureter where it merges into the renal “duplex,” with the top part connected to AND pelvis. These events are mediated by the an obstructed ureter with an ectopic ter- protein phosphatase, calcineurin,58 and mination in the or , The shaft of the embryonic ureter ini- by AngII signaling.59 Mice genetically and the bottom part connected to a re- tially comprises an epithelial tube ex- engineered to lack key molecules in the fluxing ureter that inserts too laterally in tending through loose mesenchyme. This ureteric SM-differentiation pathway have the bladder wall.1 Vesicoureteric reflux epithelium acts as a the common phenotype of hydroureter/ affects at least 0.5% of births, with center, driving surrounding cells to dif- hydronephrosis. This arises not from an- some estimates of incidence an order of ferentiate into smooth muscle (SM).52 atomic obstruction but because of a back- magnitude higher.64 Sometimes these The urothelium secretes SHH, a growth up of urine in a functionally obstructed malformations occur as part of a syn- factor that binds to the PTCH1 receptor tube lacking normal peristaltic waves. drome affecting other parts of the in immediately adjacent mesenchymal Forming a network within the SM body,67 whereas at other times, the renal cells, stimulating them to proliferate.53 layers are neural-like, KIT receptor tyro- lesions occur in isolation. Peri-urothelial mesenchymal cells are sine kinase expressing cells that are re- Knowledge of how specific molecules also stimulated to express BMP4, which quired for generation of contraction control ureter development helps us itself effects their own differentiation waves beginning before birth.60 Notably, understand why of certain into SM.51,53 Here, BMP4 enhances in- the explanted fetal ureter, even when genes cause human disease. Fraser syn- tracellular levels of phospho-SMADs43,54 physically disconnected from the kidney drome often features bilateral ureter and and upregulates TSHZ3, a transcription and bladder, undergoes regular peristalsis renal agenesis and can be caused by factor–like protein. TSHZ3 is needed for in a proximal to distal direction.43 In vivo, biallelic mutations of either FRAS1 or MYOCD expression within nascent ure- peristalsis is triggered by HCN3, a hyper- FREM2, each encoding a UB basement teric SM cells. MYOCD, a transcriptional polarization-activated cation channel ex- membrane protein.37,68 Furthermore, coactivator, then upregulates genes cod- pressed in the /kidney junc- mutations of RET are implicated in hu- ing for muscle contractile proteins, such tion.61 When hedgehog signaling is mans with similarly severe renal tract mal- as smooth muscle actin and myosin downregulated experimentally in this re- formations.69 Mutations in ROBO2 are heavy chains.43,52 Lack of another tran- gion, expression of KIT and HCN3 are reported in individuals born with reflux- scription factor, SOX9, which like compromised and contractions are per- ing and/or duplicated ureters.70 Congeni- TSHZ3, is normally expressed by mesen- turbed, even though SM cells themselves tally dilated ureters can occur in humans chyme aggregating around the urothelial appear intact.62 The mature ureter also who have mutations of SOX9 (in Campo- ureteric tube, also leads to failed SM contains adrenergic, cholinergic, nitrer- melic dysplasia) or GLI3 (Pallister-Hall differentiation.55 gic, and sensory , the activities of syndrome), encoding a transcription fac- The aggregation of SM precursor cells which modify its contractility.63 tor involved in SHH signaling. By analogy around urothelia depends on mesenchy- A theoretical scheme, in which the with the mouse models described earlier, mal expression of TBX18 and, in mice onset of fetal urine production by the one may postulate that such ureters may engineered to lack this transcription kidney enhances ureteric SM differentia- be obstructed functionally because of un- factor, prospective SM precursors become tion and function, is depicted in Figure 3. differentiated and/or poorly functioning mislocalized to the surface of the meta- MS bundles. nephros.42 Correct orientation of ureteric In the uro-facial syndrome features SM cells depends on DLGH1, an intracel- IMPLICATIONS FOR vesicoureteric reflux and dysfunctional lular scaffolding protein highly expressed UNDERSTANDING HUMAN urinary tract contractility.71 These indi- in urothelia and more weakly in nascent CONGENITAL URETER viduals have mutations of HPSE2,which SM cells.56 When DLGH1 is inactivated, MALFORMATIONS codes for heparanase-2, a protein of sim- circular muscle bundles misalign in a lon- ilar structure to classic heparanase.71 gitudinal orientation. In mutant embryos The human ureter is affected by several Both genes are expressed in the fetal lacking this protein, the differentiation of types of malformation.52,64,65 The most ureter and bladder,71 where they are

22 Journal of the American Society of Nephrology J Am Soc Nephrol 24: 19–25, 2013 www.jasn.org BRIEF REVIEW postulated to regulate neuromuscular Table 1. Transcripts with strong and REFERENCES functional differentiation. UPK3A mu- specific ureteric expression in tations have been reported in humans developing mice, as reported in the 1. Mackie GG, Stephens FD: Duplex kidneys: A born with ureteric malformations47 re- GUDMAP database correlation of renal dysplasia with position of the ureteral orifice. JUrol114: 274–280, sembling those described in mice genet- Esrrb (estrogen-related receptor-b) 1975 Hnf4g (hepatocyte nuclear factor 4g) ically engineered to lack the encoded ur- 2. Kume T, Deng K, Hogan BL: Murine fork- Hoxa1 (Homeobox1a) othelial plaque protein. 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