Skip to main content

Advertisement

Log in

Ciliogenesis in normal human kidney development and post-natal life

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Ciliogenesis in developing and post-natal human kidneys appears to influence cell proliferation and differentiation, apico–basal cell polarity, and tubular lumen formation. We have analyzed the appearance of primary cilia and differentiation of kidney cells in ten human conceptuses aged 6–22 weeks and in one 5-year-old kidney, using a double immunofluorescence labeling technique for α-tubulin, γ-tubulin, Oct-4, and Ki-67 and by electron microscopy. Immature forms of nephrons and ampullae were characterized by intense cell proliferation, which subsequently decreased during development. Primary cilia appeared on the surfaces of non-proliferating cells in developing nephrons, gradually increasing in length from 0.59 μm in renal vesicles to 0.81 μm in the S-forms of nephrons, ultimately reaching 3.04 μm in length in mature fetal and post-natal nephrons. Ciliary length increased from 0.59 μm in ampullae to 1.28 μm in post-natal collecting tubules. Mesenchymal to epithelial transformation of kidney cells coincided with the appearance of apico–basal polarity, both gap and tight junctions, and lumen formation. Up-regulation of Oct-4 expression correlated with the onset of kidney cell differentiation. Our results demonstrate the importance of proper primary cilia lengthening and Oct-4 expression for the normal development of fetal and post-natal kidneys and of apico–basal polarity for normal tubular lumen formation. Disturbances in these processes are associated with ciliopathies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Moritz KM, Wintour EM, Black MJ, Bertram JF, Caruana G (2008) Factors influencing mammalian kidney development: implications for health in adult life. Adv Anat Embryol Cell Biol 196:1–78

    Article  PubMed  CAS  Google Scholar 

  2. Carev D, Krnic D, Saraga M, Sapunar D, Saraga-Babic M (2006) Role of mitotic, pro-apoptotic and anti-apoptotic factors in human kidney development. Pediatr Nephrol 21:627–636

    Article  PubMed  Google Scholar 

  3. Eggenschwiler JT, Anderson KV (2007) Cilia and developmental signaling. Annu Rev Cell Dev Biol 23:345–373

    Article  PubMed  CAS  Google Scholar 

  4. D'Angelo A, Franco B (2011) The primary cilium in different tissues-lessons from patients and animal models. Pediatr Nephrol 26:655–662

    Google Scholar 

  5. Poole CA, Zhang ZJ, Ross JM (2001) The differential distribution of acetylated and detyrosinated alpha-tubulin in the microtubular cytoskeleton and primary cilia of hyaline cartilage chondrocytes. J Anat 199:393–405

    Article  PubMed  CAS  Google Scholar 

  6. Kim SK, Shindo A, Park TJ, Oh EC, Ghosh S, Gray RS, Lewis RA, Johnson CA, Attie-Bittach T, Katsanis N, Wallingford JB (2010) Planar cell polarity acts through septins to control collective cell movement and ciliogenesis. Science 329:1337–1340

    Article  PubMed  CAS  Google Scholar 

  7. Qin H, Diener DR, Geimer S, Cole DG, Rosenbaum JL (2004) Intraflagellar transport (IFT) cargo: IFT transports flagellar precursors to the tip and turnover products to the cell body. J Cell Biol 164:255–266

    Article  PubMed  CAS  Google Scholar 

  8. Sloboda RD, Rosenbaum JL (2007) Making sense of cilia and flagella. J Cell Biol 179:575–582

    Article  PubMed  CAS  Google Scholar 

  9. Satir P, Pedersen LB, Christensen ST (2010) The primary cilium at a glance. J Cell Sci 123:499–503

    Article  PubMed  CAS  Google Scholar 

  10. Chauvet V, Tian X, Husson H, Grimm DH, Wang T, Hiesberger T, Igarashi P, Bennett AM, Ibraghimov-Beskrovnaya O, Somlo S, Caplan MJ (2004) Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus. J Clin Invest 114:1433–1443

    PubMed  CAS  Google Scholar 

  11. Simons M, Gloy J, Ganner A, Bullerkotte A, Bashkurov M, Kronig C, Schermer B, Benzing T, Cabello OA, Jenny A, Mlodzik M, Polok B, Driever W, Obara T, Walz G (2005) Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat Genet 37:537–543

    Article  PubMed  CAS  Google Scholar 

  12. Bergmann C, Fliegauf M, Bruchle NO, Frank V, Olbrich H, Kirschner J, Schermer B, Schmedding I, Kispert A, Kranzlin B, Nurnberg G, Becker C, Grimm T, Girschick G, Lynch SA, Kelehan P, Senderek J, Neuhaus TJ, Stallmach T, Zentgraf H, Nurnberg P, Gretz N, Lo C, Lienkamp S, Schafer T, Walz G, Benzing T, Zerres K, Omran H (2008) Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. Am J Hum Genet 82:959–970

    Article  PubMed  CAS  Google Scholar 

  13. Schneider L, Cammer M, Lehman J, Nielsen SK, Guerra CF, Veland IR, Stock C, Hoffmann EK, Yoder BK, Schwab A, Satir P, Christensen ST (2010) Directional cell migration and chemotaxis in wound healing response to PDGF-AA are coordinated by the primary cilium in fibroblasts. Cell Physiol Biochem 25:279–292

    Article  PubMed  CAS  Google Scholar 

  14. Badano JL, Mitsuma N, Beales PL, Katsanis N (2006) The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 7:125–148

    Article  PubMed  CAS  Google Scholar 

  15. Lancaster MA, Gleeson JG (2009) The primary cilium as a cellular signaling center: lessons from disease. Curr Opin Genet Dev 19:220–229

    Article  PubMed  CAS  Google Scholar 

  16. Carev D, Saraga M, Saraga-Babic M (2008) Involvement of FGF and BMP family proteins and VEGF in early human kidney development. Histol Histopathol 23:853–862

    PubMed  Google Scholar 

  17. Schluter MA, Margolis B (2009) Apical lumen formation in renal epithelia. J Am Soc Nephrol 20:1444–1452

    Article  PubMed  Google Scholar 

  18. Olsen O, Funke L, Long JF, Fukata M, Kazuta T, Trinidad JC, Moore KA, Misawa H, Welling PA, Burlingame AL, Zhang M, Bredt DS (2007) Renal defects associated with improper polarization of the CRB and DLG polarity complexes in MALS-3 knockout mice. J Cell Biol 179:151–164

    Article  PubMed  CAS  Google Scholar 

  19. Ichimura K, Kurihara H, Sakai T (2010) Primary cilia disappear in rat podocytes during glomerular development. Cell Tissue Res 341:197–209

    Article  PubMed  Google Scholar 

  20. Verghese E, Weidenfeld R, Bertram JF, Ricardo SD, Deane JA (2008) Renal cilia display length alterations following tubular injury and are present early in epithelial repair. Nephrol Dial Transplant 23:834–841

    Article  PubMed  Google Scholar 

  21. Kiprilov EN, Awan A, Desprat R, Velho M, Clement CA, Byskov AG, Andersen CY, Satir P, Bouhassira EE, Christensen ST, Hirsch RE (2008) Human embryonic stem cells in culture possess primary cilia with hedgehog signaling machinery. J Cell Biol 180:897–904

    Article  PubMed  CAS  Google Scholar 

  22. Tai MH, Chang CC, Kiupel M, Webster JD, Olson LK, Trosko JE (2005) Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis. Carcinogenesis 26:495–502

    Article  PubMed  CAS  Google Scholar 

  23. Romio L, Fry AM, Winyard PJ, Malcolm S, Woolf AS, Feather SA (2004) OFD1 is a centrosomal/basal body protein expressed during mesenchymal-epithelial transition in human nephrogenesis. J Am Soc Nephrol 15:2556–2568

    Article  PubMed  CAS  Google Scholar 

  24. Carev D, Saraga M, Saraga-Babic M (2008) Expression of intermediate filaments, EGF and TGF-alpha in early human kidney development. J Mol Histol 39:227–235

    Article  PubMed  CAS  Google Scholar 

  25. Yoder BK (2007) Role of primary cilia in the pathogenesis of polycystic kidney disease. J Am Soc Nephrol 18:1381–1388

    Article  PubMed  CAS  Google Scholar 

  26. Wilson PD (2008) Mouse models of polycystic kidney disease. Curr Top Dev Biol 84:311–350

    Article  PubMed  CAS  Google Scholar 

  27. Williams JR (2008) The Declaration of Helsinki and public health. Bull World Health Organ 86:650–652

    Article  PubMed  Google Scholar 

  28. O'Rahilly R (1972) Guide to the staging of human embryos. Anat Anz 130:556–559

    PubMed  Google Scholar 

  29. Vukojevic K, Carev D, Sapunar D, Petrovic D, Saraga-Babic M (2008) Developmental patterns of caspase-3, bax and bcl-2 proteins expression in the human spinal ganglia. J Mol Histol 39:339–349

    Article  PubMed  CAS  Google Scholar 

  30. Vukojevic K, Skobic H, Saraga-Babic M (2009) Proliferation and differentiation of glial and neuronal progenitors in the development of human spinal ganglia. Differentiation 78:91–98

    Article  PubMed  CAS  Google Scholar 

  31. Reynolds ES (1963) The use of lead citrate at high pH as an electron-opaque stain in electron microscopy. J Cell Biol 17:208–212

    Article  PubMed  CAS  Google Scholar 

  32. Veland IR, Awan A, Pedersen LB, Yoder BK, Christensen ST (2009) Primary cilia and signaling pathways in mammalian development, health and disease. Nephron Physiol 111:p39–p53

    Article  PubMed  CAS  Google Scholar 

  33. Esteban MA, Harten SK, Tran MG, Maxwell PH (2006) Formation of primary cilia in the renal epithelium is regulated by the von Hippel-Lindau tumor suppressor protein. J Am Soc Nephrol 17:1801–1806

    Article  PubMed  CAS  Google Scholar 

  34. Sharma N, Berbari NF, Yoder BK (2008) Ciliary dysfunction in developmental abnormalities and diseases. Curr Top Dev Biol 85:371–427

    Article  PubMed  CAS  Google Scholar 

  35. Bisgrove BW, Yost HJ (2006) The roles of cilia in developmental disorders and disease. Development 133:4131–4143

    Article  PubMed  CAS  Google Scholar 

  36. Hildebrandt F, Attanasio M, Otto E (2009) Nephronophthisis: disease mechanisms of a ciliopathy. J Am Soc Nephrol 20:23–35

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

The authors declare the absence of any external financial interest in the information contained in this article.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mirna Saraga-Babić.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Saraga-Babić, M., Vukojević, K., Bočina, I. et al. Ciliogenesis in normal human kidney development and post-natal life. Pediatr Nephrol 27, 55–63 (2012). https://doi.org/10.1007/s00467-011-1941-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-011-1941-7

Keywords

Navigation