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Chromosoma

, Volume 116, Issue 3, pp 227–235 | Cite as

The granulocyte nucleus and lamin B receptor: avoiding the ovoid

  • Katrin Hoffmann
  • Karl Sperling
  • Ada L. Olins
  • Donald E. Olins
Review

Abstract

The major human blood granulocyte, the neutrophil, is an essential component of the innate immunity system, emigrating from blood vessels and migrating through tight tissue spaces to the site of bacterial or fungal infection where they kill and phagocytose invading microbes. Since the late nineteenth century, it has been recognized that the human neutrophil nucleus is distinctly not ovoid as in other cell types, but possesses a lobulated (segmented) shape. This deformable nucleus enhances rapid migration. Recent studies have demonstrated that lamin B receptor (LBR) is necessary for the non-ovoid shape. LBR is an integral membrane protein of the nuclear envelope. A single dominant mutation in humans leads to neutrophils with hypolobulated nuclei (Pelger–Huet anomaly); homozygosity leads to ovoid granulocyte nuclei. Interestingly, LBR is also an enzyme involved in cholesterol metabolism. Homozygosity for null mutations is frequently lethal and associated with severe skeletal deformities. In addition to the necessity for LBR, formation of the mature granulocyte nucleus also depends upon lamin composition and microtubule integrity. These observations are part of a larger question on the relationships between nuclear shape and cellular function.

Keywords

Nuclear Envelope Cholesterol Biosynthesis Skeletal Dysplasia Nuclear Shape Nuclear Envelope Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgment

We dedicate this paper to Prof. H. Stobbe (Charite, Berlin) on the occasion of his 85th birthday. Prof. Stobbe, together with K. Kaps, correctly predicted the increased prevalence of PHA in the village Gelenau from the existence of a single PHA homozygous individual. This facilitated the mapping and identification of the PHA gene in later decades. We would also like to thank L. Shultz (Jackson Laboratory, Bar Harbor, ME, USA), the Max Planck Institute for Molecular Genetics in Berlin, T. Lindner, and H. Herrmann for their ongoing creative and pleasant collaborations. K.H. is a recipient of the Rahel Hirsch scholarship provided by the medical faculty at the Charité Humboldt University, Berlin. K.H. and K.S. are supported by DFG grants SP 144/18 and SFB 577/A9. A.L.O. and D.E.O. wish to thank Bowdoin College for providing laboratory facilities and stimulating colleagues. A.L.O. and D.E.O. are supported by NIH/NHLBI R15 HL075809.

References

  1. Antony AC (2000) Megaloblastic anemias. In: Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P (eds) Hematology basic principles and practice. Churchill Livingstone, New York, pp 446–485Google Scholar
  2. Baehner RL (2000) Normal neutrophil structure and function. In: Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P (eds) Hematology basic principles and practice. Churchill Livingstone, New York, pp 667–686Google Scholar
  3. Bainton DF, Ullyot JL, Farquhar MG (1971) The development of neutrophilic polymorphonuclear leukocytes in human bone marrow. J Exp Med 134:907–934PubMedCrossRefGoogle Scholar
  4. Begemann NH, van Lookeren Campagne A (1952) Homozygous form of Pelger–Huet’s nuclear anomaly in man. Acta Haematol 7:295–303Google Scholar
  5. Bennati AM, Castelli M, Della Fazia MA, Beccari T, Caruso D, Servillo G, Roberti R (2006) Sterol dependent regulation of human TM7SF2 gene expression: role of the encoded 3beta-hydroxysterol delta(14)-reductase in human cholesterol biosynthesisGoogle Scholar
  6. Biermann H, Pietz B, Dreier R, Schmid KW, Sorg C, Sunderkotter C (1999) Murine leukocytes with ring-shaped nuclei include granulocytes, monocytes, and their precursors. J Leukoc Biol 65:217–231PubMedGoogle Scholar
  7. Bowles CA, Alsaker RD, Wolfle TL (1979) Studies of the Pelger–Huet anomaly in foxhounds. Am J Pathol 96:237–247PubMedGoogle Scholar
  8. Bracegirdle B (1978) A history of microtechnique. Cornell University Press, IthacaGoogle Scholar
  9. Carmel R, Green R, Rosenblatt DS, Watkins D (2003) Update on cobalamin, folate, and homocysteine. Hematology/the Education Program of the American Society of Hematology. Hematology 2003(1):62–81CrossRefGoogle Scholar
  10. Carter TC, Phillips RS (1950) Ichthyosis, a new recessive mutant in the house mouse. J Hered 41:297–300Google Scholar
  11. Curnutte JT, Coates TD (2000) Disorders of phagocyte function and number. In: Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P (eds) Hematology basic principles and practice. Churchill Livingstone, New York, pp 720–762Google Scholar
  12. Edens HA, Parkos CA (2003) Neutrophil transendothelial migration and alteration in vascular permeability: focus on neutrophil-derived azurocidin. Curr Opin Hematol 10:25–30PubMedCrossRefGoogle Scholar
  13. Ellenberg J, Siggia ED, Moreira JE, Smith CL, Presley JF, Worman HJ, Lippincott-Schwartz J (1997) Nuclear membrane dynamics and reassembly in living cells: targeting of an inner nuclear membrane protein in interphase and mitosis. J Cell Biol 138:1193–1206PubMedCrossRefGoogle Scholar
  14. Feng D, Nagy JA, Pyne K, Dvorak HF, Dvorak AM (1998) Neutrophils emigrate from venules by a transendothelial cell pathway in response to FMLP. J Exp Med 187:903–915PubMedCrossRefGoogle Scholar
  15. Goetz JA, Suber LM, Zeng X, Robbins DJ (2002) Sonic hedgehog as a mediator of long-range signaling. Bioessays 24:157–165PubMedCrossRefGoogle Scholar
  16. Green MC, Shultz LD, Nedzi LA (1975) Abnormal nuclear morphology of leukocytes in the mouse mutant ichthyosis. Transplantation 20:172–175PubMedCrossRefGoogle Scholar
  17. Gruenbaum Y, Margalit A, Goldman RD, Shumaker DK, Wilson KL (2005) The nuclear lamina comes of age. Nat Rev Mol Cell Biol 6:21–31PubMedCrossRefGoogle Scholar
  18. Hallett M (1989) The neutrophil: cellular biochemistry and physiology. CRC Press, Boca Raton, FLGoogle Scholar
  19. Harm H (1953) Beeinflussung des weissen Blutbildes von Pelger- und Nicht-Pelger-Kaninchen durch Colchicin. Acta Haematol 10:96–105PubMedGoogle Scholar
  20. Himmelweit F (ed) (1956) The collected papers of Paul Ehrlich. Pergamon, LondonGoogle Scholar
  21. Hoffmann K, Dreger CK, Olins AL, Olins DE, Shultz LD, Lucke B, Karl H, Kaps R, Muller D, Vaya A, Aznar J, Ware RE, Sotelo Cruz N, Lindner TH, Herrmann H, Reis A, Sperling K (2002) Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger–Huet anomaly). Nat Genet 31:410–414PubMedGoogle Scholar
  22. Holmer L, Worman HJ (2001) Inner nuclear membrane proteins: functions and targeting. Cell Mol Life Sci 58:1741–1747PubMedCrossRefGoogle Scholar
  23. Huët G (1931) Familiaire anomalie der leucocyten. Ned Tijdschr Geneeskd 75:4959Google Scholar
  24. Hughes AB (1959) A history of cytology. Abelard–Schuman, LondonGoogle Scholar
  25. Johnson CA, Bass DA, Trillo AA, Snyder MS, DeChatelet LR (1980) Functional and metabolic studies of polymorphonuclear leukocytes in the congenital Pelger–Huet anomaly. Blood 55:466–469PubMedGoogle Scholar
  26. Johnson-Leger C, Aurrand-Lions M, Imhof BA (2000) The parting of the endothelium: miracle, or simply a junctional affair? J Cell Sci 113(Pt 6):921–933PubMedGoogle Scholar
  27. Kanoh T (1991) Ring neutrophils in plasma cell dyscrasia. Arch Pathol Lab Med 115:178–180PubMedGoogle Scholar
  28. Karni RJ, Wangh LJ, Sanchez JA (2001) Nonrandom location and orientation of the inactive X chromosome in human neutrophil nuclei. Chromosoma 110:267–274PubMedGoogle Scholar
  29. Kiss M, Komar G Jr (1967) Pelger–Huet nuclear anomaly in leukocytes in a dog. Berl Münch Tierärztl Wochenschr 80:474–476PubMedGoogle Scholar
  30. Latimer KS, Rakich PM, Thompson DF (1985) Pelger–Huet anomaly in cats. Vet Pathol 22:370–374PubMedGoogle Scholar
  31. Latimer KS, Duncan JR, Kircher IM (1987) Nuclear segmentation, ultrastructure, and cytochemistry of blood cells from dogs with Pelger–Huet anomaly. J Comp Pathol 97:61–72PubMedCrossRefGoogle Scholar
  32. Makatsori D, Kourmouli N, Polioudaki H, Shultz LD, McLean K, Theodoropoulos PA, Singh PB, Georgatos SD (2004) The inner nuclear membrane protein lamin B receptor forms distinct microdomains and links epigenetically marked chromatin to the nuclear envelope. J Biol Chem 279:25567–25573PubMedCrossRefGoogle Scholar
  33. Martins SB, Eide T, Steen RL, Jahnsen T, Skalhegg BS, Collas P (2000) HA95 is a protein of the chromatin and nuclear matrix regulating nuclear envelope dynamics. J Cell Sci 113(Pt 21):3703–3713PubMedGoogle Scholar
  34. Matsumoto T, Harada Y, Yamaguchi K, Matsuzaki H, Sanada I, Yoshimura T, Honda M, Tanaka R (1984) Cytogenetic and functional studies of leukocytes with Pelger–Huet anomaly. Acta Haematol 72:264–273PubMedCrossRefGoogle Scholar
  35. Melcer S, Gruenbaum Y (2006) Nuclear morphology: when round kernels do the Charleston. Curr Biol 16:R195–R197PubMedCrossRefGoogle Scholar
  36. Metchnikoff E (1905) Immunity in infective diseases. Cambridge University Press, LondonGoogle Scholar
  37. Middleton J, Patterson AM, Gardner L, Schmutz C, Ashton BA (2002) Leukocyte extravasation: chemokine transport and presentation by the endothelium. Blood 100:3853–3860PubMedCrossRefGoogle Scholar
  38. Nachtsheim H (1943) Die Pelger-Anomalie und ihre vererbung bei Mensch und Tier. Die Erbarzt 11:129–142Google Scholar
  39. Olins AL, Olins DE (2004) Cytoskeletal influences on nuclear shape in granulocytic HL-60 cells. BMC Cell Biol 5:30PubMedCrossRefGoogle Scholar
  40. Olins AL, Olins DE (2005a) The mechanism of granulocyte nuclear shape determination: possible involvement of the centrosome. Eur J Cell Biol 84:181–188PubMedCrossRefGoogle Scholar
  41. Olins DE, Olins AL (2005b) Granulocyte heterochromatin: defining the epigenome. BMC Cell Biol [electronic resource] 6:39CrossRefGoogle Scholar
  42. Olins AL, Buendia B, Herrmann H, Lichter P, Olins DE (1998) Retinoic acid induction of nuclear envelope-limited chromatin sheets in HL-60. Exp Cell Res 245:91–104PubMedCrossRefGoogle Scholar
  43. Olins AL, Herrmann H, Lichter P, Kratzmeier M, Doenecke D, Olins DE (2001) Nuclear envelope and chromatin compositional differences comparing undifferentiated and retinoic acid- and phorbol ester-treated HL-60 cells. Exp Cell Res 268:115–127PubMedCrossRefGoogle Scholar
  44. Oosterwijk JC, Mansour S, van Noort G, Waterham HR, Hall CM, Hennekam RC (2003) Congenital abnormalities reported in Pelger–Huet homozygosity as compared to Greenberg/HEM dysplasia: highly variable expression of allelic phenotypes. J Med Genet 40:937–941PubMedCrossRefGoogle Scholar
  45. Ostlund C, Sullivan T, Stewart CL, Worman HJ (2006) Dependence of diffusional mobility of integral inner nuclear membrane proteins on A-type lamins. Biochemistry 45:1374–1382PubMedCrossRefGoogle Scholar
  46. Park BH, Dolen J, Snyder B (1977) Defective chemotactic migration of polymorphonuclear leukocytes in Pelger–Huet anomaly. Proc Soc Exp Biol Med 155:51–54PubMedGoogle Scholar
  47. Pelger K (1928) Demonstratie van een paar zeldzaam voorkomende typen van bloedlichaampjes en bespreking der patienten. Ned Tijdschr Geneeskd 72:1178Google Scholar
  48. Piller G (2001) Leukaemia—a brief historical review from ancient times to 1950. Br J Haematol 112:282–292PubMedCrossRefGoogle Scholar
  49. Porter FD (2003) Human malformation syndromes due to inborn errors of cholesterol synthesis. Curr Opin Pediatr 15:607–613PubMedCrossRefGoogle Scholar
  50. Ragan H (1999) Comparative hematology. In: Wintrobe’s clinical hematology. Lippincott Williams and Wilkins, Baltimore, MD, pp 2749–2763Google Scholar
  51. Schirmer EC, Florens L, Guan T, Yates JR III, Gerace L (2003) Nuclear membrane proteins with potential disease links found by subtractive proteomics. Science 301:1380–1382PubMedCrossRefGoogle Scholar
  52. Schotta G, Lachner M, Sarma K, Ebert A, Sengupta R, Reuter G, Reinberg D, Jenuwein T (2004) A silencing pathway to induce H3–K9 and H4–K20 trimethylation at constitutive heterochromatin. Genes Dev 18:1251–1262PubMedCrossRefGoogle Scholar
  53. Schrick K, Mayer U, Horrichs A, Kuhnt C, Bellini C, Dangl J, Schmidt J, Jurgens G (2000) FACKEL is a sterol C-14 reductase required for organized cell division and expansion in Arabidopsis embryogenesis. Genes Dev 14:1471–1484PubMedGoogle Scholar
  54. Shultz LD, Lyons BL, Burzenski LM, Gott B, Samuels R, Schweitzer PA, Dreger C, Herrmann H, Kalscheuer V, Olins AL, Olins DE, Sperling K, Hoffmann K (2003) Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger–Huet anomaly. Hum Mol Genet 12:61–69PubMedCrossRefGoogle Scholar
  55. Skendzel LP, Hoffman GC (1962) The Pelger anomaly of leukocytes: forty-one cases in seven families. Am J Clin Pathol 37:294–301PubMedGoogle Scholar
  56. Stobbe H (1959) A further homozygotous sign of the Pelger–Huet anomaly and a case of pseudohomozygotous pseudo-Pelger in chronic myelosis. Folia Haematol (Frankf) 4:6–21Google Scholar
  57. Stobbe H, Jorke D (1965) Befunde an homozygoten Pelger-merkmalstragern. Schweiz Med Wochenschr 95:1524–1529PubMedGoogle Scholar
  58. Takano M, Takeuchi M, Ito H, Furukawa K, Sugimoto K, Omata S, Horigome T (2002) The binding of lamin B receptor to chromatin is regulated by phosphorylation in the RS region. Eur J Biochem 269:943–953PubMedCrossRefGoogle Scholar
  59. Takano M, Koyama Y, Ito H, Hoshino S, Onogi H, Hagiwara M, Furukawa K, Horigome T (2004) Regulation of binding of lamin B receptor to chromatin by SR protein kinase and cdc2 kinase in Xenopus egg extracts. J Biol Chem 279:13265–13271PubMedCrossRefGoogle Scholar
  60. Undritz E (1939) Das Pelger-Huëtsche Blutbild beim Tier und seine Bedeutung für die Entwicklungsgeschichte des Blutes. Schweiz Med Wochenschr 69:1177–1186Google Scholar
  61. Undritz E (1943) Das ausschliessliche vorkommen reifer rundkerniger Leukozyten bei der reingezuechteten Pelger–Huetschen anomalie des kaninchens und die bedeutung der Pelger-leukozyten in der vergleichenden Haematologie. Folia Haematol (Frankf) 67:249–291Google Scholar
  62. Wagner N, Weber D, Seitz S, Krohne G (2004) The lamin B receptor of Drosophila melanogaster. J Cell Sci 117:2015–2028PubMedCrossRefGoogle Scholar
  63. Waterham HR, Koster J, Mooyer P, Noort Gv G, Kelley RI, Wilcox WR, Wanders RJ, Hennekam RC, Oosterwijk JC (2003) Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene. Am J Hum Genet 72:1013–1017PubMedCrossRefGoogle Scholar
  64. Worman HJ, Yuan J, Blobel G, Georgatos SD (1988) A lamin B receptor in the nuclear envelope. Proc Natl Acad Sci USA 85:8531–8534PubMedCrossRefGoogle Scholar
  65. Ye Q, Barton RM, Worman HJ (1998) Nuclear lamin-binding proteins. Sub-cell Biochem 31:587–610Google Scholar
  66. Zhang X, Kluger Y, Nakayama Y, Poddar R, Whitney C, DeTora A, Weissman SM, Newburger PE (2004) Gene expression in mature neutrophils: early responses to inflammatory stimuli. J Leukoc Biol 75:358–372PubMedCrossRefGoogle Scholar
  67. Zucker-Franklin D (1968) Electron microscopic studies of human granulocytes: structural variations related to function. Semin Hematol 5:109–133PubMedGoogle Scholar
  68. Zucker-Franklin D (1975) Physiological and pathological variations in the ultrastructure of neutrophils and monocytes. Clin Haematol 4:485–508PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Katrin Hoffmann
    • 1
  • Karl Sperling
    • 1
  • Ada L. Olins
    • 2
  • Donald E. Olins
    • 2
  1. 1.Department of Medical GeneticsCharite Humboldt UniversityBerlinGermany
  2. 2.Biology DepartmentBowdoin CollegeBrunswickUSA

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