Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Jul 15;98(2):451–459. doi: 10.1172/JCI118811

The PAX2 tanscription factor is expressed in cystic and hyperproliferative dysplastic epithelia in human kidney malformations.

P J Winyard 1, R A Risdon 1, V R Sams 1, G R Dressler 1, A S Woolf 1
PMCID: PMC507449  PMID: 8755656

Abstract

Human dysplastic kidneys are developmental aberrations which are responsible for many of the very young children with chronic renal failure. They contain poorly differentiated metanephric cells in addition to metaplastic elements. We recently demonstrated that apoptosis was prominent in undifferentiated cells around dysplastic tubules (Winyard, P.J.D., J. Nauta, D.S. Lirenman, P. Hardman, V.R. Sams, R.A. Risdon, and A.S. Woolf. 1996. Kidney Int. 49:135-146), perhaps explaining the tendency of some of these organs to regress. In contrast, apoptosis was rare in dysplastic epithelia which are thought to be ureteric bud malformations. On occasion, these tubules form cysts which distend the abdominal cavity (the multicystic dysplastic kidney) and dysplastic kidneys may rarely become malignant. We now demonstrate that dysplastic tubules maintain a high rate of proliferation postnatally and that PAX2, a potentially oncogenic transcription factor, is expressed in these epithelia. In contrast, both cell proliferation and PAX2 are downregulated during normal maturation of human collecting ducts. We demonstrate that BCL2, a protein which prevents apoptosis in renal mesenchymal to epithelia] conversion, is expressed ectopically in dysplastic kidney epithelia. We propose that dysplastic cyst formation may be understood in terms of aberrant temporal and spatial expression of master genes which are tightly regulated in the normal program of human nephrogenesis.

Full Text

The Full Text of this article is available as a PDF (796.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barr F. G., Galili N., Holick J., Biegel J. A., Rovera G., Emanuel B. S. Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma. Nat Genet. 1993 Feb;3(2):113–117. doi: 10.1038/ng0293-113. [DOI] [PubMed] [Google Scholar]
  2. Barrett D. M., Wineland R. E. Renal cell carcinoma in multicystic dysplastic kidney. Urology. 1980 Feb;15(2):152–154. doi: 10.1016/0090-4295(80)90408-2. [DOI] [PubMed] [Google Scholar]
  3. Battin J., Lacombe D., Leng J. J. Familial occurrence of hereditary renal adysplasia with müllerian anomalies. Clin Genet. 1993 Jan;43(1):23–24. doi: 10.1111/j.1399-0004.1993.tb04420.x. [DOI] [PubMed] [Google Scholar]
  4. Bravo R., Frank R., Blundell P. A., Macdonald-Bravo H. Cyclin/PCNA is the auxiliary protein of DNA polymerase-delta. Nature. 1987 Apr 2;326(6112):515–517. doi: 10.1038/326515a0. [DOI] [PubMed] [Google Scholar]
  5. Cromie W. J., Engelstein M. S., Duckett J. W., Jr Nodular renal blastema, renal dysplasia and duplicated collecting systems. J Urol. 1980 Jan;123(1):100–102. doi: 10.1016/s0022-5347(17)55800-0. [DOI] [PubMed] [Google Scholar]
  6. Dressler G. R., Deutsch U., Chowdhury K., Nornes H. O., Gruss P. Pax2, a new murine paired-box-containing gene and its expression in the developing excretory system. Development. 1990 Aug;109(4):787–795. doi: 10.1242/dev.109.4.787. [DOI] [PubMed] [Google Scholar]
  7. Dressler G. R., Douglass E. C. Pax-2 is a DNA-binding protein expressed in embryonic kidney and Wilms tumor. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1179–1183. doi: 10.1073/pnas.89.4.1179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dressler G. R., Wilkinson J. E., Rothenpieler U. W., Patterson L. T., Williams-Simons L., Westphal H. Deregulation of Pax-2 expression in transgenic mice generates severe kidney abnormalities. Nature. 1993 Mar 4;362(6415):65–67. doi: 10.1038/362065a0. [DOI] [PubMed] [Google Scholar]
  9. Dungan J. S., Fernandez M. T., Abbitt P. L., Thiagarajah S., Howards S. S., Hogge W. A. Multicystic dysplastic kidney: natural history of prenatally detected cases. Prenat Diagn. 1990 Mar;10(3):175–182. doi: 10.1002/pd.1970100307. [DOI] [PubMed] [Google Scholar]
  10. Eccles M. R., Wallis L. J., Fidler A. E., Spurr N. K., Goodfellow P. J., Reeve A. E. Expression of the PAX2 gene in human fetal kidney and Wilms' tumor. Cell Growth Differ. 1992 May;3(5):279–289. [PubMed] [Google Scholar]
  11. Ehrich J. H., Rizzoni G., Brunner F. P., Fassbinder W., Geerlings W., Mallick N. P., Raine A. E., Selwood N. H., Tufveson G. Renal replacement therapy for end-stage renal failure before 2 years of age. Nephrol Dial Transplant. 1992;7(12):1171–1177. doi: 10.1093/ndt/7.12.1171. [DOI] [PubMed] [Google Scholar]
  12. Fickenscher H. R., Chalepakis G., Gruss P. Murine Pax-2 protein is a sequence-specific trans-activator with expression in the genital system. DNA Cell Biol. 1993 Jun;12(5):381–391. doi: 10.1089/dna.1993.12.381. [DOI] [PubMed] [Google Scholar]
  13. Gnarra J. R., Dressler G. R. Expression of Pax-2 in human renal cell carcinoma and growth inhibition by antisense oligonucleotides. Cancer Res. 1995 Sep 15;55(18):4092–4098. [PubMed] [Google Scholar]
  14. Goulding M. D., Chalepakis G., Deutsch U., Erselius J. R., Gruss P. Pax-3, a novel murine DNA binding protein expressed during early neurogenesis. EMBO J. 1991 May;10(5):1135–1147. doi: 10.1002/j.1460-2075.1991.tb08054.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gruss P., Walther C. Pax in development. Cell. 1992 May 29;69(5):719–722. doi: 10.1016/0092-8674(92)90281-g. [DOI] [PubMed] [Google Scholar]
  16. Halder G., Callaerts P., Gehring W. J. Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila. Science. 1995 Mar 24;267(5205):1788–1792. doi: 10.1126/science.7892602. [DOI] [PubMed] [Google Scholar]
  17. Hanai T., Usuda N., Morita T., Shimizu T., Nagata T. Proliferative activity in the kidneys of aging mice evaluated by PCNA/cyclin immunohistochemistry. Cell Mol Biol (Noisy-le-grand) 1993 Mar;39(2):181–191. [PubMed] [Google Scholar]
  18. Hanson I. M., Seawright A., Hardman K., Hodgson S., Zaletayev D., Fekete G., van Heyningen V. PAX6 mutations in aniridia. Hum Mol Genet. 1993 Jul;2(7):915–920. doi: 10.1093/hmg/2.7.915. [DOI] [PubMed] [Google Scholar]
  19. Hockenbery D., Nuñez G., Milliman C., Schreiber R. D., Korsmeyer S. J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990 Nov 22;348(6299):334–336. doi: 10.1038/348334a0. [DOI] [PubMed] [Google Scholar]
  20. Hyatt G. A., Schmitt E. A., Marsh-Armstrong N., McCaffery P., Dräger U. C., Dowling J. E. Retinoic acid establishes ventral retinal characteristics. Development. 1996 Jan;122(1):195–204. doi: 10.1242/dev.122.1.195. [DOI] [PubMed] [Google Scholar]
  21. Kanwar Y. S., Liu Z. Z., Kumar A., Wada J., Carone F. A. Cloning of mouse c-ros renal cDNA, its role in development and relationship to extracellular matrix glycoproteins. Kidney Int. 1995 Nov;48(5):1646–1659. doi: 10.1038/ki.1995.460. [DOI] [PubMed] [Google Scholar]
  22. Keller S. A., Jones J. M., Boyle A., Barrow L. L., Killen P. D., Green D. G., Kapousta N. V., Hitchcock P. F., Swank R. T., Meisler M. H. Kidney and retinal defects (Krd), a transgene-induced mutation with a deletion of mouse chromosome 19 that includes the Pax2 locus. Genomics. 1994 Sep 15;23(2):309–320. doi: 10.1006/geno.1994.1506. [DOI] [PubMed] [Google Scholar]
  23. Kreidberg J. A., Sariola H., Loring J. M., Maeda M., Pelletier J., Housman D., Jaenisch R. WT-1 is required for early kidney development. Cell. 1993 Aug 27;74(4):679–691. doi: 10.1016/0092-8674(93)90515-r. [DOI] [PubMed] [Google Scholar]
  24. Larsson S. H., Charlieu J. P., Miyagawa K., Engelkamp D., Rassoulzadegan M., Ross A., Cuzin F., van Heyningen V., Hastie N. D. Subnuclear localization of WT1 in splicing or transcription factor domains is regulated by alternative splicing. Cell. 1995 May 5;81(3):391–401. doi: 10.1016/0092-8674(95)90392-5. [DOI] [PubMed] [Google Scholar]
  25. Maizels M., Simpson S. B., Jr Primitive ducts of renal dysplasia induced by culturing ureteral buds denuded of condensed renal mesenchyme. Science. 1983 Feb 4;219(4584):509–510. doi: 10.1126/science.6823548. [DOI] [PubMed] [Google Scholar]
  26. Matsuo T., Osumi-Yamashita N., Noji S., Ohuchi H., Koyama E., Myokai F., Matsuo N., Taniguchi S., Doi H., Iseki S. A mutation in the Pax-6 gene in rat small eye is associated with impaired migration of midbrain crest cells. Nat Genet. 1993 Apr;3(4):299–304. doi: 10.1038/ng0493-299. [DOI] [PubMed] [Google Scholar]
  27. Maulbecker C. C., Gruss P. The oncogenic potential of Pax genes. EMBO J. 1993 Jun;12(6):2361–2367. doi: 10.1002/j.1460-2075.1993.tb05890.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Max E. E., Wakatsuki Y., Neurath M. F., Strober W. The role of BSAP in immunoglobulin isotype switching and B-cell proliferation. Curr Top Microbiol Immunol. 1995;194:449–458. doi: 10.1007/978-3-642-79275-5_52. [DOI] [PubMed] [Google Scholar]
  29. Mugrauer G., Ekblom P. Contrasting expression patterns of three members of the myc family of protooncogenes in the developing and adult mouse kidney. J Cell Biol. 1991 Jan;112(1):13–25. doi: 10.1083/jcb.112.1.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Mundlos S., Pelletier J., Darveau A., Bachmann M., Winterpacht A., Zabel B. Nuclear localization of the protein encoded by the Wilms' tumor gene WT1 in embryonic and adult tissues. Development. 1993 Dec;119(4):1329–1341. doi: 10.1242/dev.119.4.1329. [DOI] [PubMed] [Google Scholar]
  31. Novack D. V., Korsmeyer S. J. Bcl-2 protein expression during murine development. Am J Pathol. 1994 Jul;145(1):61–73. [PMC free article] [PubMed] [Google Scholar]
  32. Oltvai Z. N., Milliman C. L., Korsmeyer S. J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993 Aug 27;74(4):609–619. doi: 10.1016/0092-8674(93)90509-o. [DOI] [PubMed] [Google Scholar]
  33. Phelps D. E., Dressler G. R. Identification of novel Pax-2 binding sites by chromatin precipitation. J Biol Chem. 1996 Apr 5;271(14):7978–7985. doi: 10.1074/jbc.271.14.7978. [DOI] [PubMed] [Google Scholar]
  34. Plachov D., Chowdhury K., Walther C., Simon D., Guenet J. L., Gruss P. Pax8, a murine paired box gene expressed in the developing excretory system and thyroid gland. Development. 1990 Oct;110(2):643–651. doi: 10.1242/dev.110.2.643. [DOI] [PubMed] [Google Scholar]
  35. Poleev A., Wendler F., Fickenscher H., Zannini M. S., Yaginuma K., Abbott C., Plachov D. Distinct functional properties of three human paired-box-protein, PAX8, isoforms generated by alternative splicing in thyroid, kidney and Wilms' tumors. Eur J Biochem. 1995 Mar 15;228(3):899–911. doi: 10.1111/j.1432-1033.1995.tb20338.x. [DOI] [PubMed] [Google Scholar]
  36. Pritchard-Jones K., Fleming S., Davidson D., Bickmore W., Porteous D., Gosden C., Bard J., Buckler A., Pelletier J., Housman D. The candidate Wilms' tumour gene is involved in genitourinary development. Nature. 1990 Jul 12;346(6280):194–197. doi: 10.1038/346194a0. [DOI] [PubMed] [Google Scholar]
  37. Qiao J., Cohen D., Herzlinger D. The metanephric blastema differentiates into collecting system and nephron epithelia in vitro. Development. 1995 Oct;121(10):3207–3214. doi: 10.1242/dev.121.10.3207. [DOI] [PubMed] [Google Scholar]
  38. Read A. P. Pax genes--paired feet in three camps. Nat Genet. 1995 Apr;9(4):333–334. doi: 10.1038/ng0495-333. [DOI] [PubMed] [Google Scholar]
  39. Risdon R. A. Renal dysplasia. I. A clinico-pathological study of 76 cases. J Clin Pathol. 1971 Feb;24(1):57–71. doi: 10.1136/jcp.24.1.57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Rothenpieler U. W., Dressler G. R. Pax-2 is required for mesenchyme-to-epithelium conversion during kidney development. Development. 1993 Nov;119(3):711–720. doi: 10.1242/dev.119.3.711. [DOI] [PubMed] [Google Scholar]
  41. Ryan G., Steele-Perkins V., Morris J. F., Rauscher F. J., 3rd, Dressler G. R. Repression of Pax-2 by WT1 during normal kidney development. Development. 1995 Mar;121(3):867–875. doi: 10.1242/dev.121.3.867. [DOI] [PubMed] [Google Scholar]
  42. Santos O. F., Barros E. J., Yang X. M., Matsumoto K., Nakamura T., Park M., Nigam S. K. Involvement of hepatocyte growth factor in kidney development. Dev Biol. 1994 Jun;163(2):525–529. doi: 10.1006/dbio.1994.1169. [DOI] [PubMed] [Google Scholar]
  43. Sanyanusin P., McNoe L. A., Sullivan M. J., Weaver R. G., Eccles M. R. Mutation of PAX2 in two siblings with renal-coloboma syndrome. Hum Mol Genet. 1995 Nov;4(11):2183–2184. doi: 10.1093/hmg/4.11.2183. [DOI] [PubMed] [Google Scholar]
  44. Sanyanusin P., Schimmenti L. A., McNoe L. A., Ward T. A., Pierpont M. E., Sullivan M. J., Dobyns W. B., Eccles M. R. Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux. Nat Genet. 1995 Apr;9(4):358–364. doi: 10.1038/ng0495-358. [DOI] [PubMed] [Google Scholar]
  45. Sariola H., Saarma M., Sainio K., Arumäe U., Palgi J., Vaahtokari A., Thesleff I., Karavanov A. Dependence of kidney morphogenesis on the expression of nerve growth factor receptor. Science. 1991 Oct 25;254(5031):571–573. doi: 10.1126/science.1658930. [DOI] [PubMed] [Google Scholar]
  46. Sharma P. M., Bowman M., Yu B. F., Sukumar S. A rodent model for Wilms tumors: embryonal kidney neoplasms induced by N-nitroso-N'-methylurea. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9931–9935. doi: 10.1073/pnas.91.21.9931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Song D. L., Chalepakis G., Gruss P., Joyner A. L. Two Pax-binding sites are required for early embryonic brain expression of an Engrailed-2 transgene. Development. 1996 Feb;122(2):627–635. doi: 10.1242/dev.122.2.627. [DOI] [PubMed] [Google Scholar]
  48. Sorenson C. M., Rogers S. A., Korsmeyer S. J., Hammerman M. R. Fulminant metanephric apoptosis and abnormal kidney development in bcl-2-deficient mice. Am J Physiol. 1995 Jan;268(1 Pt 2):F73–F81. doi: 10.1152/ajprenal.1995.268.1.F73. [DOI] [PubMed] [Google Scholar]
  49. Stapleton P., Weith A., Urbánek P., Kozmik Z., Busslinger M. Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9. Nat Genet. 1993 Apr;3(4):292–298. doi: 10.1038/ng0493-292. [DOI] [PubMed] [Google Scholar]
  50. Tassabehji M., Read A. P., Newton V. E., Patton M., Gruss P., Harris R., Strachan T. Mutations in the PAX3 gene causing Waardenburg syndrome type 1 and type 2. Nat Genet. 1993 Jan;3(1):26–30. doi: 10.1038/ng0193-26. [DOI] [PubMed] [Google Scholar]
  51. Threadgill D. W., Dlugosz A. A., Hansen L. A., Tennenbaum T., Lichti U., Yee D., LaMantia C., Mourton T., Herrup K., Harris R. C. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science. 1995 Jul 14;269(5221):230–234. doi: 10.1126/science.7618084. [DOI] [PubMed] [Google Scholar]
  52. Torres M., Gómez-Pardo E., Dressler G. R., Gruss P. Pax-2 controls multiple steps of urogenital development. Development. 1995 Dec;121(12):4057–4065. doi: 10.1242/dev.121.12.4057. [DOI] [PubMed] [Google Scholar]
  53. Veis D. J., Sorenson C. M., Shutter J. R., Korsmeyer S. J. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell. 1993 Oct 22;75(2):229–240. doi: 10.1016/0092-8674(93)80065-m. [DOI] [PubMed] [Google Scholar]
  54. Wallin J., Eibel H., Neubüser A., Wilting J., Koseki H., Balling R. Pax1 is expressed during development of the thymus epithelium and is required for normal T-cell maturation. Development. 1996 Jan;122(1):23–30. doi: 10.1242/dev.122.1.23. [DOI] [PubMed] [Google Scholar]
  55. Winyard P. J., Nauta J., Lirenman D. S., Hardman P., Sams V. R., Risdon R. A., Woolf A. S. Deregulation of cell survival in cystic and dysplastic renal development. Kidney Int. 1996 Jan;49(1):135–146. doi: 10.1038/ki.1996.18. [DOI] [PubMed] [Google Scholar]
  56. Woolf A. S. Clinical impact and biological basis of renal malformations. Semin Nephrol. 1995 Jul;15(4):361–371. [PubMed] [Google Scholar]
  57. Woolf A. S., Kolatsi-Joannou M., Hardman P., Andermarcher E., Moorby C., Fine L. G., Jat P. S., Noble M. D., Gherardi E. Roles of hepatocyte growth factor/scatter factor and the met receptor in the early development of the metanephros. J Cell Biol. 1995 Jan;128(1-2):171–184. doi: 10.1083/jcb.128.1.171. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES