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Vol. 78, No. 4, 2011
Issue release date: July 2011
Section title: Original Paper
Pathobiology 2011;78:210–219
(DOI:10.1159/000326769)

Lim1, an Embryonal Transcription Factor, Is Absent in Multicystic Renal Dysplasia, but Reactivated in Nephroblastomas

Guertl B.a · Senanayake U.a · Nusshold E.a · Leuschner I.c · Mannweiler S.a · Ebner B.b · Hoefler G.a
aInstitute of Pathology and bCentre of Medical Research, Medical University of Graz, Graz, Austria; cKiel Paediatric Tumor Registry, Department of Paediatric Pathology, University of Kiel, Kiel, Germany
email Corresponding Author

Abstract

Objective:Lim1 (Lim homeobox 1) plays an important role during rodent renal development; however, its rolein human kidney development and disease is still unclear. Methods: We investigated LIM1 expression during human renal development, in dysplastic kidneys and in renal neoplasms using immunohistochemistry. RNA levels in renal carcinomas were determined by quantitative RT-PCR, and the potential roles of LIM1 in mesenchymal-epithelial transition and cell cycle were investigated in a cell culture model. Results: LIM1 was detected in pretubular aggregates, S-shaped and comma-shaped bodies as well as immature glomeruli between 10 and 30 weeks of gestation. Eleven dysplastic kidneys showed no expression of LIM1. In contrast, 12 of 32 nephroblastomas showed nuclear positivity. One regressive nephroblastoma had diffuse expression of LIM1 in tubular structures, all others showed focal positivity in mesenchymal, blastemal and epithelial structures. Renal cell carcinomas revealed no expression of LIM1. Overexpression of LIM1 in a cell culture model led to an increase in KERATIN7 expression but no change in the cell cycle. Conclusion: Our study supports the concept of a causative role of LIM1 deficiency in the development of multicystic kidney. In a small subset of nephroblastomas with a more diffuse expression pattern LIM1 might also contribute to the pathogenesis of these lesions.

© 2011 S. Karger AG, Basel


  

Key Words

  • LIM1
  • Multicystic renal dysplasia
  • Nephroblastoma
  • Renal cell carcinoma
  • Mesenchymal-epithelial transition
  • PAX2

References

  1. Parham DM, Qualman SJ, Teot L, Barr FG, Morotti R, Sorensen PH, Triche TJ, Meyer WH: Correlation between histology and PAX/FKHR fusion status in alveolar rhabdomyosarcoma: a report from the Children’s Oncology Group. Am J Surg Pathol 2007;31:895–901.

    External Resources

  2. Lovvorn HN, Westrup J, Opperman S, Boyle S, Shi G, Anderson J, Perlman EJ, Perantoni AO, Wills M, de Caestecker M: CITED1 expression in Wilms’ tumor and embryonic kidney. Neoplasia 2007;9:589–600.
  3. Eccles MR, Yun K, Reeve AE, Fidler AE: Comparative in situ hybridization analysis of PAX2, PAX8, and WT1 gene transcription in human fetal kidney and Wilms’ tumors. Am J Pathol 1995;146:40–45.
  4. Dressler GR: The cellular basis of kidney development. Annu Rev Cell Dev Biol 2006;22:509–529.
  5. Kobayashi A, Kwan KM, Carroll TJ, McMahon AP, Mendelsohn CL, Behringer RR: Distinct and sequential tissue specific activities of the LIM-class homeobox gene Lim1 for tubular morphogenesis during kidney development. Development 2005;132:2809–2823.
  6. Fujii TA, Kveta Cecklova, Gilbert DJ, Copeland NG, Jenkins NA, Westphal H: Genomic structure and chromosomal location of the murine LIM class homeobox gene Lhx1. Mamm Genome 1998;9:81–83.
  7. Phillips JC: Assignment of LHX1 to human chromosome bands 17q11.2→q12 by use of radiation hybrid mapping and somatic cell hybridization. Cytogenet Genome Res 2002;97:140D.
  8. Karavanov AA, Karavanova I, Peratoni A, Dawid IB: Expression pattern of the rat Lim-1 homeobox gene suggests a dual role during kidney development. Int J Dev Biol 1998;42:61–66.
  9. Shawlot W, Behringer RR: Requirement for Lim1 in head-organizer function. Nature 1995;374:425–430.
  10. Kobayashi A, Shawlot W, Kania A Behringer RR: Requirement of Lim1 for female reproductive tract development. Development 2004;131:539–549.
  11. Pedersen A, Skjong C, Shawlot W: Lim1 is required for nephric duct extension and ureteric bud morphogenesis. Dev Biol 2005;288:571–581.
  12. Hunter CS, Rhodes SJ: Lim-homeodomain genes in mammalian development and human disease. Mol Biol Rep 2005;32:67–77.
  13. Sredni ST, Gadd S, Huang CC, Breslow N, Grundy P, Green DM, Dome JS, Shamberger RC, Beckwith JB, Perlman EJ: Subsets of very low risk Wilms tumor show distinctive gene expression, histologic and clinical features. Clin Cancer Res 2009;15:6800–6809.
  14. Guertl B, Ratschek M, Harms D, Jaenig U, Leuschner I, Poremba C, Hoefler G Clonality and loss of heterozygosity of WT genes are early events in the pathogenesis of nephroblastomas. Hum Pathol 2003;34:278–281.
  15. Taylor LM, James A, Schuller CE, Brce J, Lock RB, Mackenzie KL: Inactivation of p16INK4a, with retention of pRB and p53/p21cip1 function, in human MRC5 fibroblasts that overcome a telomere-independent crisis during immortalization. J Biol Chem 2004;279:43634–43645.
  16. Saxen L, Sariola H: Early organogenesis of the kidney. Pediatr Nephrol 1987;1:385–392.
  17. Dressler GR, Woolf AS: Pax2 in kidney development and renal disease. Int J Dev Biol 1999;43:463–468.
  18. Bernstein J, Risdon RA: Kidneys and urinary tract; in Gilbert-Barness E (ed): Potter’s Pathology of the Fetus and Infant, ed 1. St. Louis, Mosby, 1997, vol 2, pp 875–879.
  19. Woolf AS: The life of the human kidney before birth: its secret unfolds. Pediatr Res 2001;49:8–10.
  20. Winyard PJD, Risdon RA, Sams VR, Dressler GR, Woolf AS: The PAX2 transcriptionfactor is expressed in cystic and hyperproliferative dysplastic epithelia in human kidney malformations. J Clin Invest 1996;98:451–459.
  21. Woolf AS, Winyard PJ: Gene expression and cell turnover in human renal dysplasia. Histol Histopathol 2000;15:159–166.
  22. Ulinski T, Lescure S, Beaufils S, Guigonis V, Decramer S, Morin D, Clauin S, Deschenes B, Bouissou F, Bensman A, Bellanne-Chantelot C: Renal phenotypes related to hepatocate nuclear factor-1β (TCF2) mutations in a pediatric cohort. J Am Soc Nephrol 2006;17:497–503.
  23. Jain S, Suarez AA, McGuire J, Liapis H: Expression profiles of congenital renal dysplasia reveal new insights into renal development and disease. Pediatr Nephrol 2007;22:962–974.

    External Resources

  24. Bernadini L, Gimelli S, Gervasini C, Carella M, Baban A, Frontino G, Barbano G, Divizia MT, Fedele L, Novelli A, Béna F, Lalatta F, Miozzo M, Dallapiccola B: Recurrent microdeletion at 17q12 as a cause of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome: two case reports. Orphanet J Rare Dis 2009;4:25.

    External Resources

  25. Reidy KJ, Rosenblum ND: Cell and molecular biology of kidney development. Semin Nephrol 2009;29:321–337.
  26. Narlis M, Grote D, Gaitan Y, Boualia SK, Bouchard M: Pax2 and Pax8 regulate branching morphogenesis and nephron differentiation in the developing kidney. J Am Soc Nephrol 2007;18:1121–1129.
  27. Dressler GR, Douglass EC: Pax-2 is a DNA-binding protein expression in embryonic kidney and Wilms tumor. Proc Natl Acad Sci USA 1992;89:1179–1183.
  28. Dekel B, Metsuyanim S, Schmidt-Ott KM, Fridman E, Jacob-Hirsch J, Simon A, Pinthus J, Mor Y, Barasch J, Amariglio N, Reisner Y, Kaminski N, Rechavi G: Multiple imprinted and stemness genes provide a link between normal and tumor progenitor cells of the developing human kidney. Cancer Res 2006;66:6040–6049.
  29. Dormoy V, Danilin S, Lindner V, Thomas L, Rothhut S, Coquard C, Helwig JJ, Jacqmin D, Lang H, Massfelder T: The sonic hedgehog signalling pathway is reactivated in human renal cell carcinoma and plays orchestral role in tumor growth. Mol Cancer 2009;8:123.

    External Resources

  30. Oczan A, Zhai Q, Javed R, Shen SS, Coffey D, Krishnan B, Truong LD: PAX-2 is a helpful marker for diagnosing metastatic renal cell carcinoma. Arch Pathol Lab Med 2010;134:1121–1129.
  31. Memeo L, Jhang J, Assaad AM, McKiernan JM, Murty VVVS, Hibsoosh H, Tong GX, Manuskhani MM: Immunohistochemical analysis for cytokeratin 7, KIT and PAX2. Am J Clin Pathol 2007;127:225–229.

    External Resources

  32. Chu PG, Weiss LM: Keratin expression in human tissues and neoplasms. Histopathology 2002;40:403–439.
  33. Grill C, Guelly C, Ebner B, Leuschner I, Hauser-Kronberger C, Hoefler G, Guertl B: Loss of PTEN/MMAC1 activity is a rare and late event in the pathogenesis of nephroblastomas. Hum Pathol 2010;41:1172–1177.

  

Author Contacts

Barbara Guertl, MD
Institute of Pathology, Medical University of Graz
Auenbruggerplatz 25
AT–8036 Graz (Austria)
Tel. +43 316 385 81397, E-Mail barbara.guertl-lackner@medunigraz.at

  

Article Information

Received: September 30, 2010
Accepted after revision: February 17, 2011
Published online: July 19, 2011
Number of Print Pages : 10
Number of Figures : 4, Number of Tables : 3, Number of References : 33

  

Publication Details

Pathobiology (Exploring the basis of disease)

Vol. 78, No. 4, Year 2011 (Cover Date: July 2011)

Journal Editor: Borisch B. (Geneva), Yasui W. (Hiroshima)
ISSN: 1015-2008 (Print), eISSN: 1423-0291 (Online)

For additional information: http://www.karger.com/PAT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Objective:Lim1 (Lim homeobox 1) plays an important role during rodent renal development; however, its rolein human kidney development and disease is still unclear. Methods: We investigated LIM1 expression during human renal development, in dysplastic kidneys and in renal neoplasms using immunohistochemistry. RNA levels in renal carcinomas were determined by quantitative RT-PCR, and the potential roles of LIM1 in mesenchymal-epithelial transition and cell cycle were investigated in a cell culture model. Results: LIM1 was detected in pretubular aggregates, S-shaped and comma-shaped bodies as well as immature glomeruli between 10 and 30 weeks of gestation. Eleven dysplastic kidneys showed no expression of LIM1. In contrast, 12 of 32 nephroblastomas showed nuclear positivity. One regressive nephroblastoma had diffuse expression of LIM1 in tubular structures, all others showed focal positivity in mesenchymal, blastemal and epithelial structures. Renal cell carcinomas revealed no expression of LIM1. Overexpression of LIM1 in a cell culture model led to an increase in KERATIN7 expression but no change in the cell cycle. Conclusion: Our study supports the concept of a causative role of LIM1 deficiency in the development of multicystic kidney. In a small subset of nephroblastomas with a more diffuse expression pattern LIM1 might also contribute to the pathogenesis of these lesions.

© 2011 S. Karger AG, Basel


  

Author Contacts

Barbara Guertl, MD
Institute of Pathology, Medical University of Graz
Auenbruggerplatz 25
AT–8036 Graz (Austria)
Tel. +43 316 385 81397, E-Mail barbara.guertl-lackner@medunigraz.at

  

Article Information

Received: September 30, 2010
Accepted after revision: February 17, 2011
Published online: July 19, 2011
Number of Print Pages : 10
Number of Figures : 4, Number of Tables : 3, Number of References : 33

  

Publication Details

Pathobiology (Exploring the basis of disease)

Vol. 78, No. 4, Year 2011 (Cover Date: July 2011)

Journal Editor: Borisch B. (Geneva), Yasui W. (Hiroshima)
ISSN: 1015-2008 (Print), eISSN: 1423-0291 (Online)

For additional information: http://www.karger.com/PAT


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 9/30/2010
Accepted: 2/17/2011
Published online: 7/19/2011
Issue release date: July 2011

Number of Print Pages: 10
Number of Figures: 4
Number of Tables: 3

ISSN: 1015-2008 (Print)
eISSN: 1423-0291 (Online)

For additional information: http://www.karger.com/PAT


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Parham DM, Qualman SJ, Teot L, Barr FG, Morotti R, Sorensen PH, Triche TJ, Meyer WH: Correlation between histology and PAX/FKHR fusion status in alveolar rhabdomyosarcoma: a report from the Children’s Oncology Group. Am J Surg Pathol 2007;31:895–901.

    External Resources

  2. Lovvorn HN, Westrup J, Opperman S, Boyle S, Shi G, Anderson J, Perlman EJ, Perantoni AO, Wills M, de Caestecker M: CITED1 expression in Wilms’ tumor and embryonic kidney. Neoplasia 2007;9:589–600.
  3. Eccles MR, Yun K, Reeve AE, Fidler AE: Comparative in situ hybridization analysis of PAX2, PAX8, and WT1 gene transcription in human fetal kidney and Wilms’ tumors. Am J Pathol 1995;146:40–45.
  4. Dressler GR: The cellular basis of kidney development. Annu Rev Cell Dev Biol 2006;22:509–529.
  5. Kobayashi A, Kwan KM, Carroll TJ, McMahon AP, Mendelsohn CL, Behringer RR: Distinct and sequential tissue specific activities of the LIM-class homeobox gene Lim1 for tubular morphogenesis during kidney development. Development 2005;132:2809–2823.
  6. Fujii TA, Kveta Cecklova, Gilbert DJ, Copeland NG, Jenkins NA, Westphal H: Genomic structure and chromosomal location of the murine LIM class homeobox gene Lhx1. Mamm Genome 1998;9:81–83.
  7. Phillips JC: Assignment of LHX1 to human chromosome bands 17q11.2→q12 by use of radiation hybrid mapping and somatic cell hybridization. Cytogenet Genome Res 2002;97:140D.
  8. Karavanov AA, Karavanova I, Peratoni A, Dawid IB: Expression pattern of the rat Lim-1 homeobox gene suggests a dual role during kidney development. Int J Dev Biol 1998;42:61–66.
  9. Shawlot W, Behringer RR: Requirement for Lim1 in head-organizer function. Nature 1995;374:425–430.
  10. Kobayashi A, Shawlot W, Kania A Behringer RR: Requirement of Lim1 for female reproductive tract development. Development 2004;131:539–549.
  11. Pedersen A, Skjong C, Shawlot W: Lim1 is required for nephric duct extension and ureteric bud morphogenesis. Dev Biol 2005;288:571–581.
  12. Hunter CS, Rhodes SJ: Lim-homeodomain genes in mammalian development and human disease. Mol Biol Rep 2005;32:67–77.
  13. Sredni ST, Gadd S, Huang CC, Breslow N, Grundy P, Green DM, Dome JS, Shamberger RC, Beckwith JB, Perlman EJ: Subsets of very low risk Wilms tumor show distinctive gene expression, histologic and clinical features. Clin Cancer Res 2009;15:6800–6809.
  14. Guertl B, Ratschek M, Harms D, Jaenig U, Leuschner I, Poremba C, Hoefler G Clonality and loss of heterozygosity of WT genes are early events in the pathogenesis of nephroblastomas. Hum Pathol 2003;34:278–281.
  15. Taylor LM, James A, Schuller CE, Brce J, Lock RB, Mackenzie KL: Inactivation of p16INK4a, with retention of pRB and p53/p21cip1 function, in human MRC5 fibroblasts that overcome a telomere-independent crisis during immortalization. J Biol Chem 2004;279:43634–43645.
  16. Saxen L, Sariola H: Early organogenesis of the kidney. Pediatr Nephrol 1987;1:385–392.
  17. Dressler GR, Woolf AS: Pax2 in kidney development and renal disease. Int J Dev Biol 1999;43:463–468.
  18. Bernstein J, Risdon RA: Kidneys and urinary tract; in Gilbert-Barness E (ed): Potter’s Pathology of the Fetus and Infant, ed 1. St. Louis, Mosby, 1997, vol 2, pp 875–879.
  19. Woolf AS: The life of the human kidney before birth: its secret unfolds. Pediatr Res 2001;49:8–10.
  20. Winyard PJD, Risdon RA, Sams VR, Dressler GR, Woolf AS: The PAX2 transcriptionfactor is expressed in cystic and hyperproliferative dysplastic epithelia in human kidney malformations. J Clin Invest 1996;98:451–459.
  21. Woolf AS, Winyard PJ: Gene expression and cell turnover in human renal dysplasia. Histol Histopathol 2000;15:159–166.
  22. Ulinski T, Lescure S, Beaufils S, Guigonis V, Decramer S, Morin D, Clauin S, Deschenes B, Bouissou F, Bensman A, Bellanne-Chantelot C: Renal phenotypes related to hepatocate nuclear factor-1β (TCF2) mutations in a pediatric cohort. J Am Soc Nephrol 2006;17:497–503.
  23. Jain S, Suarez AA, McGuire J, Liapis H: Expression profiles of congenital renal dysplasia reveal new insights into renal development and disease. Pediatr Nephrol 2007;22:962–974.

    External Resources

  24. Bernadini L, Gimelli S, Gervasini C, Carella M, Baban A, Frontino G, Barbano G, Divizia MT, Fedele L, Novelli A, Béna F, Lalatta F, Miozzo M, Dallapiccola B: Recurrent microdeletion at 17q12 as a cause of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome: two case reports. Orphanet J Rare Dis 2009;4:25.

    External Resources

  25. Reidy KJ, Rosenblum ND: Cell and molecular biology of kidney development. Semin Nephrol 2009;29:321–337.
  26. Narlis M, Grote D, Gaitan Y, Boualia SK, Bouchard M: Pax2 and Pax8 regulate branching morphogenesis and nephron differentiation in the developing kidney. J Am Soc Nephrol 2007;18:1121–1129.
  27. Dressler GR, Douglass EC: Pax-2 is a DNA-binding protein expression in embryonic kidney and Wilms tumor. Proc Natl Acad Sci USA 1992;89:1179–1183.
  28. Dekel B, Metsuyanim S, Schmidt-Ott KM, Fridman E, Jacob-Hirsch J, Simon A, Pinthus J, Mor Y, Barasch J, Amariglio N, Reisner Y, Kaminski N, Rechavi G: Multiple imprinted and stemness genes provide a link between normal and tumor progenitor cells of the developing human kidney. Cancer Res 2006;66:6040–6049.
  29. Dormoy V, Danilin S, Lindner V, Thomas L, Rothhut S, Coquard C, Helwig JJ, Jacqmin D, Lang H, Massfelder T: The sonic hedgehog signalling pathway is reactivated in human renal cell carcinoma and plays orchestral role in tumor growth. Mol Cancer 2009;8:123.

    External Resources

  30. Oczan A, Zhai Q, Javed R, Shen SS, Coffey D, Krishnan B, Truong LD: PAX-2 is a helpful marker for diagnosing metastatic renal cell carcinoma. Arch Pathol Lab Med 2010;134:1121–1129.
  31. Memeo L, Jhang J, Assaad AM, McKiernan JM, Murty VVVS, Hibsoosh H, Tong GX, Manuskhani MM: Immunohistochemical analysis for cytokeratin 7, KIT and PAX2. Am J Clin Pathol 2007;127:225–229.

    External Resources

  32. Chu PG, Weiss LM: Keratin expression in human tissues and neoplasms. Histopathology 2002;40:403–439.
  33. Grill C, Guelly C, Ebner B, Leuschner I, Hauser-Kronberger C, Hoefler G, Guertl B: Loss of PTEN/MMAC1 activity is a rare and late event in the pathogenesis of nephroblastomas. Hum Pathol 2010;41:1172–1177.