The granulocyte nucleus and lamin B receptor: avoiding the ovoid

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.

[1]  R. Hennekam,et al.  Congenital abnormalities reported in Pelger-Huët homozygosity as compared to Greenberg/HEM dysplasia: highly variable expression of allelic phenotypes , 2003, Journal of medical genetics.

[2]  G. Kómár,et al.  [Pelger-Huet nuclear anomaly in leukocytes in a dog]. , 1967, Berliner und Munchener tierarztliche Wochenschrift.

[3]  L. Wangh,et al.  Nonrandom location and orientation of the inactive X chromosome in human neutrophil nuclei , 2001, Chromosoma.

[4]  T. Kanoh Ring neutrophils in plasma cell dyscrasia. , 1991, Archives of pathology & laboratory medicine.

[5]  Danny Reinberg,et al.  A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. , 2004, Genes & development.

[6]  H. Dvorak,et al.  Neutrophils Emigrate from Venules by a Transendothelial Cell Pathway in Response to FMLP , 1998, The Journal of experimental medicine.

[7]  D. Weber,et al.  The lamin B receptor of Drosophila melanogaster , 2004, Journal of Cell Science.

[8]  John R Yates,et al.  Nuclear Membrane Proteins with Potential Disease Links Found by Subtractive Proteomics , 2003, Science.

[9]  D. E. Olins,et al.  Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger-Huët anomaly. , 2003, Human molecular genetics.

[10]  M. Hagiwara,et al.  Regulation of Binding of Lamin B Receptor to Chromatin by SR Protein Kinase and cdc2 Kinase in Xenopus Egg Extracts* , 2004, Journal of Biological Chemistry.

[11]  D. E. Olins,et al.  Retinoic acid induction of nuclear envelope-limited chromatin sheets in HL-60. , 1998, Experimental cell research.

[12]  Howard J. Worman,et al.  Nuclear Membrane Dynamics and Reassembly in Living Cells: Targeting of an Inner Nuclear Membrane Protein in Interphase and Mitosis , 1997, The Journal of cell biology.

[13]  B. Snyder,et al.  Defective Chemotactic Migration of Polymorphonuclear Leukocytes in Pelger-Huet Anomaly , 1977, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[14]  T. Carter,et al.  ICHTHYOSIS, A NEW RECESSIVE MUTANTIn the House Mouse , 1950 .

[15]  Yuval Kluger,et al.  Gene expression in mature neutrophils: early responses to inflammatory stimuli , 2004, Journal of leukocyte biology.

[16]  D. E. Olins,et al.  Granulocyte heterochromatin: defining the epigenome , 2005, BMC Cell Biology.

[17]  D. E. Olins,et al.  The mechanism of granulocyte nuclear shape determination: possible involvement of the centrosome. , 2005, European journal of cell biology.

[18]  T. Matsumoto,et al.  Cytogenetic and functional studies of leukocytes with Pelger-Huët anomaly. , 1984, Acta haematologica.

[19]  L. Koss On the history of cytology. , 1980, Acta cytologica.

[20]  Katherine L. Wilson,et al.  The nuclear lamina comes of age , 2005, Nature Reviews Molecular Cell Biology.

[21]  C. Parkos,et al.  Neutrophil transendothelial migration and alteration in vascular permeability: focus on neutrophil-derived azurocidin , 2003, Current opinion in hematology.

[22]  D. E. Olins,et al.  Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger–Huët anomaly) , 2002, Nature Genetics.

[23]  L. Nedzi,et al.  Abnormal nuclear morphology of leukocytes in the mouse mutant ichthyosis. , 1975, Transplantation.

[24]  L. Gardner,et al.  Leukocyte extravasation: chemokine transport and presentation by the endothelium. , 2002, Blood.

[25]  F. Porter Human malformation syndromes due to inborn errors of cholesterol synthesis. , 2003, Current opinion in pediatrics.

[26]  H. Worman,et al.  Nuclear lamin-binding proteins. , 1998, Sub-cellular biochemistry.

[27]  D. Zucker‐Franklin Physiological and pathological variations in the ultrastructure of neutrophils and monocytes. , 1975, Clinics in Haematology.

[28]  G. C. Hoffman,et al.  The Pelger anomaly of leukocytes: forty-one cases in seven families. , 1962, American journal of clinical pathology.

[29]  M. Wintrobe [The megaloblastic anemias]. , 1960, Il Policlinico. Sezione pratica.

[30]  R. Green,et al.  Update on cobalamin, folate, and homocysteine. , 2003, Hematology. American Society of Hematology. Education Program.

[31]  C. Johnson,et al.  Functional and metabolic studies of polymorphonuclear leukocytes in the congenital Pelger-Huet anomaly. , 1980, Blood.

[32]  D. E. Olins,et al.  Nuclear envelope and chromatin compositional differences comparing undifferentiated and retinoic acid- and phorbol ester-treated HL-60 cells. , 2001, Experimental cell research.

[33]  H. Worman,et al.  Inner nuclear membrane proteins: functions and targeting , 2001, Cellular and Molecular Life Sciences CMLS.

[34]  R. Hennekam,et al.  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. , 2003, American journal of human genetics.

[35]  G. Blobel,et al.  A lamin B receptor in the nuclear envelope. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[36]  T. Beccari,et al.  Sterol dependent regulation of human TM7SF2 gene expression: role of the encoded 3beta-hydroxysterol Delta14-reductase in human cholesterol biosynthesis. , 2006, Biochimica et biophysica acta.

[37]  K. Schrick,et al.  FACKEL is a sterol C-14 reductase required for organized cell division and expansion in Arabidopsis embryogenesis. , 2000, Genes & development.

[38]  K. Latimer,et al.  Nuclear segmentation, ultrastructure, and cytochemistry of blood cells from dogs with Pelger-Huët anomaly. , 1987, Journal of comparative pathology.

[39]  D. Makatsori,et al.  The Inner Nuclear Membrane Protein Lamin B Receptor Forms Distinct Microdomains and Links Epigenetically Marked Chromatin to the Nuclear Envelope* , 2004, Journal of Biological Chemistry.

[40]  M. Hallett The Neutrophil: Cellular Biochemistry and Physiology , 1989 .

[41]  Elie Metchnikoff,et al.  IMMUNITY IN INFECTIVE DISEASES , 1906 .

[42]  K. Latimer,et al.  Pelger-Huët Anomaly in Cats , 1985, Veterinary pathology.

[43]  C. Bowles,et al.  Studies of the Pelger-Huët anomaly in foxhounds. , 1979, The American journal of pathology.

[44]  P. Collas,et al.  HA95 is a protein of the chromatin and nuclear matrix regulating nuclear envelope dynamics. , 2000, Journal of cell science.

[45]  H. Waterham,et al.  Autosomal Recessive HEM/Greenberg Skeletal Dysplasia Is Caused by 3β-Hydroxysterol Δ14-Reductase Deficiency Due to Mutations in the Lamin B Receptor Gene , 2003 .

[46]  H. Stobbe,et al.  [Findings in homozygous carriers of Pelger's anomaly]. , 1965, Schweizerische medizinische Wochenschrift.

[47]  D. Zucker‐Franklin Electron microscopic studies of human granulocytes: structural variations related to function. , 1968, Seminars in hematology.

[48]  D. E. Olins,et al.  Cytoskeletal influences on nuclear shape in granulocytic HL-60 cells , 2004, BMC Cell Biology.

[49]  M. Aurrand-Lions,et al.  The parting of the endothelium: miracle, or simply a junctional affair? , 2000, Journal of cell science.

[50]  N. HAVERKAMP BEGEMANN,et al.  Homozygous form of Pelger-Huët's nuclear anomaly in man. , 1952, Acta haematologica.

[51]  Shai Melcer,et al.  Nuclear Morphology: When Round Kernels Do the Charleston , 2006, Current Biology.

[52]  H. Harm Beeinflussung des weißen Blutbildes von Pelger- und Nicht-Pelger-Kaninchen durch Colchicin , 1953 .

[53]  C. Stewart,et al.  Dependence of diffusional mobility of integral inner nuclear membrane proteins on A-type lamins. , 2006, Biochemistry.

[54]  M. Farquhar,et al.  THE DEVELOPMENT OF NEUTROPHILIC POLYMORPHONUCLEAR LEUKOCYTES IN HUMAN BONE MARROW , 1971, The Journal of experimental medicine.

[55]  M. Takano,et al.  The binding of lamin B receptor to chromatin is regulated by phosphorylation in the RS region. , 2002, European journal of biochemistry.

[56]  B. Bracegirdle A history of microtechnique , 1978 .

[57]  K. Schmid,et al.  Murine leukocytes with ring-shaped nuclei include granulocytes, monocytes, and their precursors. , 1998, Journal of leukocyte biology.

[58]  G. Piller Leukaemia – a brief historical review from ancient times to 1950 , 2001, British journal of haematology.

[59]  D. Robbins,et al.  Sonic Hedgehog as a mediator of long‐range signaling * , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[60]  R. Hoffman,et al.  Hematology: Basic Principles and Practice , 1995 .

[61]  Joseph S. Fruton,et al.  The Collected Papers of Paul Ehrlich , 1957, The Yale Journal of Biology and Medicine.