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Hnf1beta and nephron segmentation

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Abstract

The nephron is the functional unit that executes the homeostatic roles of the kidney in vertebrates. Critical to this function is the physical arrangement of the glomerular blood filter attached to a tubular epithelium that is subdivided into specialized proximal and distal segments. During embryogenesis, nephron progenitors undergo a mesenchymal–epithelial transition (MET) and adopt different segment-specific cell fates along the proximo-distal axis of the nephron. The molecular basis of how these segments arise remains largely unknown. Recent studies using the zebrafish have identified the Hnf1beta transcription factor (Hnf1b) as a major regulator of tubular segmentation. In Hnf1b-deficient zebrafish embryos, nephron progenitors fail to adopt the proximo-distal segmentation pattern of the nephron, yet still undergo MET. This observation suggests that the functional segmentation of renal tubular epithelial cells is independent of pathways that induce their epithelialization. Here we review this new role of Hnf1b for nephron segmentation during zebrafish and mouse kidney development.

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References

  1. Naylor RW, Przepiorski A, Ren Q, Yu J, Davidson AJ (2013) HNF1beta is essential for nephron segmentation during nephrogenesis. J Am Soc Nephrol 24:77–87

    Article  CAS  PubMed  Google Scholar 

  2. Wingert RA, Davidson AJ (2008) The zebrafish pronephros: a model to study nephron segmentation. Kidney Int 73:1120–1127

    Article  CAS  PubMed  Google Scholar 

  3. Wingert RA, Selleck R, Yu J, Song HD, Chen Z, Song A, Zhou Y, Thisse B, Thisse C, McMahon AP, Davidson AJ (2007) The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros. PLoS Genet 3:1922–1938

    Article  CAS  PubMed  Google Scholar 

  4. Dressler GR (2006) The cellular basis of kidney development. Annu Rev Cell Dev Biol 22:509–529

    Article  CAS  PubMed  Google Scholar 

  5. Costantini F, Kopan R (2010) Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. Dev Cell 18:698–712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mah SP, Saueressig H, Goulding M, Kintner C, Dressler GR (2000) Kidney development in cadherin-6 mutants: delayed mesenchyme-to-epithelial conversion and loss of nephrons. Dev Biol 223:38–53

    Article  CAS  PubMed  Google Scholar 

  7. Davies JA, Bard JB (1996) Inductive interactions between the mesenchyme and the ureteric bud. Exp Nephrol 4:77–85

    CAS  PubMed  Google Scholar 

  8. Slanchev K, Putz M, Schmitt A, Kramer-Zucker A, Walz G (2011) Nephrocystin-4 is required for pronephric duct-dependent cloaca formation in zebrafish. Hum Mol Genet 20:3119–3128

    Article  CAS  PubMed  Google Scholar 

  9. Brunskill EW, Aronow BJ, Georgas K, Rumballe B, Valerius MT, Aronow J, Kaimal V, Jegga AG, Yu J, Grimmond S, McMahon AP, Patterson LT, Little MH, Potter SS (2008) Atlas of gene expression in the developing kidney at microanatomic resolution. Dev Cell 15:781–791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wingert RA, Davidson AJ (2011) Zebrafish nephrogenesis involves dynamic spatiotemporal expression changes in renal progenitors and essential signals from retinoic acid and irx3b. Dev Dyn 240:2011–2027

    Article  CAS  PubMed  Google Scholar 

  11. Heliot C, Desgrange A, Buisson I, Prunskaite-Hyyrylainen R, Shan J, Vainio S, Umbhauer M, Cereghini S (2013) HNF1B controls proximal-intermediate nephron segment identity in vertebrates by regulating Notch signalling components and Irx1/2. Development 140:873–885

    Article  CAS  PubMed  Google Scholar 

  12. Lokmane L, Heliot C, Garcia-Villalba P, Fabre M, Cereghini S (2010) vHNF1 functions in distinct regulatory circuits to control ureteric bud branching and early nephrogenesis. Development 137:347–357

    Article  CAS  PubMed  Google Scholar 

  13. Massa F, Garbay S, Bouvier R, Sugitani Y, Noda T, Gubler MC, Heidet L, Pontoglio M, Fischer E (2013) Hepatocyte nuclear factor 1beta controls nephron tubular development. Development 140:886–896

    Article  CAS  PubMed  Google Scholar 

  14. Nakanishi K, Yoshikawa N (2003) Genetic disorders of human congenital anomalies of the kidney and urinary tract (CAKUT). Pediatr Int 45:610–616

    Article  CAS  PubMed  Google Scholar 

  15. Thomas R, Sanna-Cherchi S, Warady BA, Furth SL, Kaskel FJ, Gharavi AG (2011) HNF1B and PAX2 mutations are a common cause of renal hypodysplasia in the CKiD cohort. Pediatr Nephrol 26:897–903

    Article  PubMed  PubMed Central  Google Scholar 

  16. Weber S, Moriniere V, Knuppel T, Charbit M, Dusek J, Ghiggeri GM, Jankauskiene A, Mir S, Montini G, Peco-Antic A, Wuhl E, Zurowska AM, Mehls O, Antignac C, Schaefer F, Salomon R (2006) Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study. J Am Soc Nephrol 17:2864–2870

    Article  CAS  PubMed  Google Scholar 

  17. Edghill EL, Stals K, Oram RA, Shepherd MH, Hattersley AT, Ellard S (2013) HNF1B deletions in patients with young-onset diabetes but no known renal disease. Diabet Med 30:114–117

    Article  CAS  PubMed  Google Scholar 

  18. Barbacci E, Reber M, Ott MO, Breillat C, Huetz F, Cereghini S (1999) Variant hepatocyte nuclear factor 1 is required for visceral endoderm specification. Development 126:4795–4805

    CAS  PubMed  Google Scholar 

  19. Coffinier C, Thepot D, Babinet C, Yaniv M, Barra J (1999) Essential role for the homeoprotein vHNF1/HNF1beta in visceral endoderm differentiation. Development 126:4785–4794

    CAS  PubMed  Google Scholar 

  20. Gresh L, Fischer E, Reimann A, Tanguy M, Garbay S, Shao X, Hiesberger T, Fiette L, Igarashi P, Yaniv M, Pontoglio M (2004) A transcriptional network in polycystic kidney disease. EMBO J 23:1657–1668

    Article  CAS  PubMed  Google Scholar 

  21. Verdeguer F, Le Corre S, Fischer E, Callens C, Garbay S, Doyen A, Igarashi P, Terzi F, Pontoglio M (2010) A mitotic transcriptional switch in polycystic kidney disease. Nat Med 16:106–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sun Z, Hopkins N (2001) vhnf1, the MODY5 and familial GCKD-associated gene, regulates regional specification of the zebrafish gut, pronephros, and hindbrain. Genes Dev 15:3217–3229

    Article  CAS  PubMed  Google Scholar 

  23. Cheng HT, Kim M, Valerius MT, Surendran K, Schuster-Gossler K, Gossler A, McMahon AP, Kopan R (2007) Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron. Development 134:801–811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bouchard M, Souabni A, Mandler M, Neubuser A, Busslinger M (2002) Nephric lineage specification by Pax2 and Pax8. Genes Dev 16:2958–2970

    Article  CAS  PubMed  Google Scholar 

  25. Dressler GR, Deutsch U, Chowdhury K, Nornes HO, Gruss P (1990) Pax2, a new murine paired-box-containing gene and its expression in the developing excretory system. Development 109:787–795

    CAS  PubMed  Google Scholar 

  26. Majumdar A, Lun K, Brand M, Drummond IA (2000) Zebrafish no isthmus reveals a role for pax2.1 in tubule differentiation and patterning events in the pronephric primordia. Development 127:2089–2098

    CAS  PubMed  Google Scholar 

  27. Pfeffer PL, Gerster T, Lun K, Brand M, Busslinger M (1998) Characterization of three novel members of the zebrafish Pax2/5/8 family: dependency of Pax5 and Pax8 expression on the Pax2.1 (noi) function. Development 125:3063–3074

    CAS  PubMed  Google Scholar 

  28. Serluca FC, Fishman MC (2001) Pre-pattern in the pronephric kidney field of zebrafish. Development 128:2233–2241

    CAS  PubMed  Google Scholar 

  29. Rothenpieler UW, Dressler GR (1993) Pax-2 is required for mesenchyme-to-epithelium conversion during kidney development. Development 119:711–720

    CAS  PubMed  Google Scholar 

  30. Alarcon P, Rodriguez-Seguel E, Fernandez-Gonzalez A, Rubio R, Gomez-Skarmeta JL (2008) A dual requirement for Iroquois genes during Xenopus kidney development. Development 135:3197–3207

    Article  CAS  PubMed  Google Scholar 

  31. Reggiani L, Raciti D, Airik R, Kispert A, Brandli AW (2007) The prepattern transcription factor Irx3 directs nephron segment identity. Genes Dev 21:2358–2370

    Article  CAS  PubMed  Google Scholar 

  32. Auyeung DJ, Kessler FK, Ritter JK (2003) Differential regulation of alternate UDP-glucuronosyltransferase 1A6 gene promoters by hepatic nuclear factor-1. Toxicol Appl Pharmacol 191:156–166

    Article  CAS  PubMed  Google Scholar 

  33. Ferre S, Veenstra GJ, Bouwmeester R, Hoenderop JG, Bindels RJ (2011) HNF-1B specifically regulates the transcription of the gammaa-subunit of the Na+/K+−ATPase. Biochem Biophys Res Commun 404:284–290

    Article  CAS  PubMed  Google Scholar 

  34. Kikuchi R, Kusuhara H, Hattori N, Kim I, Shiota K, Gonzalez FJ, Sugiyama Y (2007) Regulation of tissue-specific expression of the human and mouse urate transporter 1 gene by hepatocyte nuclear factor 1 alpha/beta and DNA methylation. Mol Pharmacol 72:1619–1625

    Article  CAS  PubMed  Google Scholar 

  35. Ma Z, Gong Y, Patel V, Karner CM, Fischer E, Hiesberger T, Carroll TJ, Pontoglio M, Igarashi P (2007) Mutations of HNF-1beta inhibit epithelial morphogenesis through dysregulation of SOCS-3. Proc Natl Acad Sci USA 104:20386–20391

    Article  CAS  PubMed  Google Scholar 

  36. Saji T, Kikuchi R, Kusuhara H, Kim I, Gonzalez FJ, Sugiyama Y (2008) Transcriptional regulation of human and mouse organic anion transporter 1 by hepatocyte nuclear factor 1 alpha/beta. J Pharmacol Exp Ther 324:784–790

    Article  CAS  PubMed  Google Scholar 

  37. Naylor RW, Jones EA (2009) Notch activates Wnt-4 signalling to control medio-lateral patterning of the pronephros. Development 136:3585–3595

    Article  CAS  PubMed  Google Scholar 

  38. McCright B (2003) Notch signaling in kidney development. Curr Opin Nephrol Hypertens 12:5–10

    Article  CAS  PubMed  Google Scholar 

  39. Boyle SC, Kim M, Valerius MT, McMahon AP, Kopan R (2011) Notch pathway activation can replace the requirement for Wnt4 and Wnt9b in mesenchymal-to-epithelial transition of nephron stem cells. Development 138:4245–4254

    Article  CAS  PubMed  Google Scholar 

  40. Cheng HT, Kopan R (2005) The role of Notch signaling in specification of podocyte and proximal tubules within the developing mouse kidney. Kidney Int 68:1951–1952

    Article  CAS  PubMed  Google Scholar 

  41. Kopan R, Cheng HT, Surendran K (2007) Molecular insights into segmentation along the proximal-distal axis of the nephron. J Am Soc Nephrol 18:2014–2020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular Medicine & Pathology, School of Medical Sciences, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    Richard W. Naylor & Alan J. Davidson

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  1. Richard W. Naylor
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  2. Alan J. Davidson
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Correspondence to Alan J. Davidson.

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Naylor, R.W., Davidson, A.J. Hnf1beta and nephron segmentation. Pediatr Nephrol 29, 659–664 (2014). https://doi.org/10.1007/s00467-013-2662-x

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  • DOI: https://doi.org/10.1007/s00467-013-2662-x

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