Gene regulatory networks directing myeloid and lymphoid cell fates within the immune system.

Considerable progress is being achieved in the analysis of gene regulatory networks that direct cell fate decisions within the hematopoietic system. In addition to transcription factors that are pivotal for cell fate specification and commitment, recent evidence suggests the involvement of microRNAs. In this review we attempt to integrate these two types of regulatory components into circuits that dictate cell fate choices leading to the generation of innate as well as adaptive immune cells. The developmental circuits are placed in the context of a revised scheme for hematopoiesis that suggests that both the innate (myeloid) and adaptive (lymphoid) lineages of the immune system arise from a common progenitor.

[1]  Pu Zhang,et al.  Potential Autoregulation of Transcription Factor PU.1 by an Upstream Regulatory Element , 2005, Molecular and Cellular Biology.

[2]  Mark J. Murphy,et al.  c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. , 2004, Genes & development.

[3]  M. Busslinger,et al.  Instructive role of the transcription factor E2A in early B lymphopoiesis and germinal center B cell development. , 2008, Immunity.

[4]  D. Bartel,et al.  MicroRNAs Modulate Hematopoietic Lineage Differentiation , 2004, Science.

[5]  A. Cumano,et al.  Thymic stromal-derived lymphopoietin distinguishes fetal from adult B cell development , 2003, Nature Immunology.

[6]  S. Orkin,et al.  Functional analysis and in vivo footprinting implicate the erythroid transcription factor GATA-1 as a positive regulator of its own promoter. , 1991, Genes & development.

[7]  M. Busslinger,et al.  Distinct Promoters Mediate the Regulation of Ebf1 Gene Expression by Interleukin-7 and Pax5 , 2006, Molecular and Cellular Biology.

[8]  A. Burgess,et al.  Mice Lacking Three Myeloid Colony-Stimulating Factors (G-CSF, GM-CSF, and M-CSF) Still Produce Macrophages and Granulocytes and Mount an Inflammatory Response in a Sterile Model of Peritonitis1 , 2007, The Journal of Immunology.

[9]  F. Morlé,et al.  Functional Cross-Antagonism between Transcription Factors FLI-1 and EKLF , 2003, Molecular and Cellular Biology.

[10]  E. Bertolino,et al.  Transcription factor EBF restricts alternative lineage options and promotes B cell fate commitment independently of Pax5 , 2008, Nature Immunology.

[11]  M. Sigvardsson,et al.  Inhibition of EBF function by active Notch signaling reveals a novel regulatory pathway in early B-cell development. , 2005, Blood.

[12]  M. Kondo,et al.  IL-7 receptor signaling is necessary for stage transition in adult B cell development through up-regulation of EBF , 2005, The Journal of experimental medicine.

[13]  Harinder Singh,et al.  Assembling a gene regulatory network for specification of the B cell fate. , 2004, Developmental cell.

[14]  I. Weissman,et al.  A clonogenic common myeloid progenitor that gives rise to all myeloid lineages , 2000, Nature.

[15]  R. Gerstein,et al.  The Earliest Step in B Lineage Differentiation from Common Lymphoid Progenitors Is Critically Dependent upon Interleukin 7 , 2002, The Journal of experimental medicine.

[16]  P. Lásló,et al.  Multilineage Transcriptional Priming and Determination of Alternate Hematopoietic Cell Fates , 2006, Cell.

[17]  Harinder Singh,et al.  Contingent gene regulatory networks and B cell fate specification. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[18]  M. Busslinger,et al.  Reversion of B Cell Commitment upon Loss of Pax5 Expression , 2002, Science.

[19]  E. Wagner,et al.  Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5 BSAP , 1994, Cell.

[20]  I. Weissman,et al.  Purification and characterization of mouse hematopoietic stem cells. , 1988, Science.

[21]  M. Busslinger,et al.  Analysis of Notch1 Function by In Vitro T Cell Differentiation of Pax5 Mutant Lymphoid Progenitors1 , 2004, The Journal of Immunology.

[22]  E. Scott,et al.  Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. , 1994, Science.

[23]  S. Ng,et al.  Early hematopoietic lineage restrictions directed by Ikaros , 2006, Nature Immunology.

[24]  D. Bartel,et al.  Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs , 2004, Nature Reviews Genetics.

[25]  S. Jacobsen,et al.  Key role of flt3 ligand in regulation of the common lymphoid progenitor but not in maintenance of the hematopoietic stem cell pool. , 2002, Immunity.

[26]  M. Busslinger,et al.  Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. , 2004, Genes & development.

[27]  S. Orkin,et al.  Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells , 2004, Nature.

[28]  P. Pandolfi,et al.  Regulation of B Versus T Lymphoid Lineage Fate Decision by the Proto-Oncogene LRF , 2007, Science.

[29]  S. Jacobsen,et al.  Upregulation of Flt3 expression within the bone marrow Lin(-)Sca1(+)c-kit(+) stem cell compartment is accompanied by loss of self-renewal capacity. , 2001, Immunity.

[30]  Daniel G Tenen,et al.  The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages. , 2006, Genes & development.

[31]  Alessandro Fatica,et al.  A Minicircuitry Comprised of MicroRNA-223 and Transcription Factors NFI-A and C/EBPα Regulates Human Granulopoiesis , 2005, Cell.

[32]  Hiroshi Kawamoto,et al.  Long-term cultured E2A-deficient hematopoietic progenitor cells are pluripotent. , 2004, Immunity.

[33]  S. Orkin,et al.  Transcription factor GATA‐1 in megakaryocyte development , 1998, Stem cells.

[34]  K. Anderson,et al.  B-lineage commitment prior to surface expression of B220 and CD19 on hematopoietic progenitor cells. , 2008, Blood.

[35]  T. Graf,et al.  B young again. , 2008, Immunity.

[36]  A. Bhandoola,et al.  The earliest thymic progenitors for T cells possess myeloid lineage potential , 2008, Nature.

[37]  R. Plasterk,et al.  The diverse functions of microRNAs in animal development and disease. , 2006, Developmental cell.

[38]  M. Busslinger,et al.  Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells. , 2006, Immunity.

[39]  Carlo M. Croce,et al.  MicroRNAs 17-5p–20a–106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation , 2007, Nature Cell Biology.

[40]  S. Akira,et al.  Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. , 2006, Immunity.

[41]  A. Cumano,et al.  Interleukin-7 is necessary to maintain the B cell potential in common lymphoid progenitors , 2005, The Journal of experimental medicine.

[42]  Lina A. Thoren,et al.  Identification of Flt3+ Lympho-Myeloid Stem Cells Lacking Erythro-Megakaryocytic Potential A Revised Road Map for Adult Blood Lineage Commitment , 2005, Cell.

[43]  H. Singh,et al.  PU.1, a shared transcriptional regulator of lymphoid and myeloid cell fates. , 1999, Cold Spring Harbor symposia on quantitative biology.

[44]  N. Rekhtman,et al.  Direct interaction of hematopoietic transcription factors PU.1 and GATA-1: functional antagonism in erythroid cells. , 1999, Genes & development.

[45]  D. Tenen,et al.  Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[46]  K. Akashi,et al.  C/EBPβ is required for 'emergency' granulopoiesis , 2006, Nature Immunology.

[47]  T. Graf,et al.  Stepwise Reprogramming of B Cells into Macrophages , 2004, Cell.

[48]  H. Weintraub,et al.  The helix-loop-helix gene E2A is required for B cell formation , 1994, Cell.

[49]  Ian Krop,et al.  E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements , 1994, Cell.

[50]  Lymphoid-restricted development from multipotent candidate murine stem cells: distinct and complimentary functions of the c-kit and flt3-ligands. , 1999 .

[51]  Irving L. Weissman,et al.  Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells , 2003, Nature.

[52]  Min Ye,et al.  Myeloid or lymphoid promiscuity as a critical step in hematopoietic lineage commitment. , 2002, Developmental cell.

[53]  R. Grosschedl,et al.  Failure of B-cell differentiation in mice lacking the transcription factor EBF , 1995, Nature.

[54]  Michael T. McManus,et al.  Gene silencing in mammals by small interfering RNAs , 2002, Nature Reviews Genetics.

[55]  Marius Wernig,et al.  Direct Reprogramming of Terminally Differentiated Mature B Lymphocytes to Pluripotency , 2008, Cell.

[56]  Ellen V Rothenberg,et al.  Negotiation of the T lineage fate decision by transcription-factor interplay and microenvironmental signals. , 2007, Immunity.

[57]  T. Ikawa,et al.  Adult T-cell progenitors retain myeloid potential , 2008, Nature.

[58]  G. Cheng,et al.  Deregulated expression of the PU.1 transcription factor blocks murine erythroleukemia cell terminal differentiation , 1997, Oncogene.

[59]  S. Orkin,et al.  Transcriptional regulation of erythropoiesis: an affair involving multiple partners , 2002, Oncogene.

[60]  Stuart H. Orkin,et al.  Diversification of haematopoietic stem cells to specific lineages , 2000, Nature Reviews Genetics.

[61]  H. Singh,et al.  Regulation of B lymphocyte and macrophage development by graded expression of PU.1. , 2000, Science.

[62]  Stephen L. Nutt,et al.  Commitment to the B-lymphoid lineage depends on the transcription factor Pax5 , 1999, Nature.

[63]  B. Kee,et al.  Early B Cell Factor Promotes B Lymphopoiesis with Reduced Interleukin 7 Responsiveness in the Absence of E2A , 2004, The Journal of experimental medicine.

[64]  M. Busslinger,et al.  Long-term in vivo reconstitution of T-cell development by Pax5-deficient B-cell progenitors , 1999, Nature.

[65]  Pu Zhang,et al.  Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha. , 2004, Immunity.

[66]  L. Zon,et al.  Hematopoiesis: An Evolving Paradigm for Stem Cell Biology , 2008, Cell.

[67]  T. Graf,et al.  GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts. , 1995, Genes & development.

[68]  W. Pear,et al.  Regulation of lymphoid development, differentiation, and function by the Notch pathway. , 2005, Annual review of immunology.

[69]  S. Orkin,et al.  PU.1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding. , 2000, Blood.

[70]  C. Croce,et al.  MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[71]  T. Graf,et al.  Determinants of lymphoid-myeloid lineage diversification. , 2006, Annual review of immunology.

[72]  A. Fatica,et al.  The interplay between the master transcription factor PU.1 and miR-424 regulates human monocyte/macrophage differentiation , 2007, Proceedings of the National Academy of Sciences.

[73]  T. Graf.  Immunology: Blood lines redrawn , 2008, Nature.

[74]  Ellen V Rothenberg,et al.  Cell lineage regulators in B and T cell development , 2007, Nature Immunology.

[75]  S. Nutt,et al.  The transcriptional regulation of B cell lineage commitment. , 2007, Immunity.

[76]  Richard Dahl,et al.  Regulation of macrophage and neutrophil cell fates by the PU.1:C/EBPα ratio and granulocyte colony-stimulating factor , 2003, Nature Immunology.

[77]  Ignacio A. Demarco,et al.  Regulation of B cell fate commitment and immunoglobulin heavy-chain gene rearrangements by Ikaros , 2008, Nature Immunology.

[78]  Nicola K. Wilson,et al.  A Two-Step, PU.1-Dependent Mechanism for Developmentally Regulated Chromatin Remodeling and Transcription of the c-fms Gene , 2006, Molecular and Cellular Biology.

[79]  K. Akashi,et al.  Reciprocal activation of GATA-1 and PU.1 marks initial specification of hematopoietic stem cells into myeloerythroid and myelolymphoid lineages. , 2007, Cell stem cell.

[80]  I. Mårtensson,et al.  Complementary Signaling through flt3 and Interleukin-7 Receptor α Is Indispensable for Fetal and Adult B Cell Genesis , 2003, The Journal of experimental medicine.

[81]  S. Goff,et al.  Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. , 1995, Immunity.

[82]  R. Grosschedl,et al.  Coordinate regulation of B cell differentiation by the transcription factors EBF and E2A. , 1999, Immunity.