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• W1968627142 abstract "The Notch signaling pathway regulates many aspects of embryonic development, as well as differentiation processes and tissue homeostasis in multiple adult organ systems. Disregulation of Notch signaling is associated with several human disorders, including cancer. In the last decade, it became evident that Notch signaling plays important roles within the hematopoietic and immune systems. Notch plays an essential role in the development of embryonic hematopoietic stem cells and influences multiple lineage decisions of developing lymphoid and myeloid cells. Moreover, recent evidence suggests that Notch is an important modulator of T cell-mediated immune responses. In this review, we discuss Notch signaling in hematopoiesis, lymphocyte development, and function as well as in T cell acute lymphoblastic leukemia. The Notch signaling pathway regulates many aspects of embryonic development, as well as differentiation processes and tissue homeostasis in multiple adult organ systems. Disregulation of Notch signaling is associated with several human disorders, including cancer. In the last decade, it became evident that Notch signaling plays important roles within the hematopoietic and immune systems. Notch plays an essential role in the development of embryonic hematopoietic stem cells and influences multiple lineage decisions of developing lymphoid and myeloid cells. Moreover, recent evidence suggests that Notch is an important modulator of T cell-mediated immune responses. In this review, we discuss Notch signaling in hematopoiesis, lymphocyte development, and function as well as in T cell acute lymphoblastic leukemia. The Notch signaling cascade is highly conserved and found in organisms as diverse as worms and humans. In 1917, the geneticist Thomas Hunt Morgan and his colleagues described fruit flies with notches at the margins of their wing blades (Morgan, 1917Morgan T.H. The theory of the gene.Am. Nat. 1917; 51: 513-544Crossref Google Scholar). It turned out that this notched wing phenotype is the result of a partial loss of function of the Drosophila Notch gene, which was cloned in the mid eighties (Kidd et al., 1986Kidd S. Kelley M.R. Young M.W. Sequence of the notch locus of Drosophila melanogaster: Relationship of the encoded protein to mammalian clotting and growth factors.Mol. Cell. Biol. 1986; 6: 3094-3108Crossref PubMed Google Scholar, Wharton et al., 1985Wharton K.A. Johansen K.M. Xu T. Artavanis-Tsakonas S. Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats.Cell. 1985; 43: 567-581Abstract Full Text PDF PubMed Google Scholar). Drosophila Notch encodes an unusual type I transmembrane receptor that is activated by two different membrane-bound ligands called Delta and Serrate. Mammals posses four Notch receptors (Notch1–4) that are bound by five ligands (Delta-like1, 3, and 4 and Jagged 1 and 2) (Figure 1; Bray, 2006Bray S.J. Notch signalling: A simple pathway becomes complex.Nat. Rev. Mol. Cell Biol. 2006; 7: 678-689Crossref PubMed Scopus (898) Google Scholar). The molecular and biochemical details of Notch signaling have recently been covered by excellent reviews (Gordon et al., 2008Gordon W.R. Arnett K.L. Blacklow S.C. The molecular logic of Notch signaling—A structural and biochemical perspective.J. Cell Sci. 2008; 121: 3109-3119Crossref PubMed Scopus (77) Google Scholar, Kopan and Ilagan, 2009Kopan R. Ilagan M.X. The canonical Notch signaling pathway: Unfolding the activation mechanism.Cell. 2009; 137: 216-233Abstract Full Text Full Text PDF PubMed Scopus (720) Google Scholar). In brief, newly synthesized Notch receptors are proteolytically cleaved in the Golgi (at site S1) during their transport to the cell surface by a furin-like protease. This cleavage generates a heterodimeric receptor consisting of an extracellular subunit (NEC) that is noncovalently linked to a second subunit containing the extracellular heterodimerization domain and the transmembrane domain followed by the cytoplasmic region of the Notch receptor (N™). The extracellular part of the receptors contains 29–36 epidermal growth factor-like repeats involved in ligand binding, followed by three cysteine-rich LIN12 repeats that prevent ligand-independent activation and a hydrophobic stretch of amino acids mediating heterodimerization between NEC and N™. The cytoplasmic tail of the receptor harbors multiple conserved elements including nuclear localization signals, as well as protein-protein interaction and transactivation domains. Notch signaling is initiated by ligand-receptor interaction between neighboring cells, leading to two successive proteolytic cleavages of the receptor. The first is mediated by metalloproteases of the ADAM family, which cleave the receptors 12–13 amino acids external to the transmembrane domain (at site S2). The shedded extracellular domain is endocytosed by the ligand-expressing cell, a process that is dependent on monoubiquitinylation of the cytoplasmic tail of the ligands by E3-ubiquitin ligases of the mind bomb and neuralized family. Ligand binding to NEC presumably induces a conformational change within the Notch receptors to expose the S2 cleavage site for proteolysis. After shedding of the extracellular domain, a second cleavage within the transmembrane domain (at site S3) is mediated by the γ-secretase activity of a multiprotein complex. This liberates the intracellular domain of Notch receptors (NICD), which subsequently traffics to the nucleus and heterodimerizes with the DNA binding transcription factor CSL in order to form a short-lived nuclear transcription complex. The transcription factor CSL is also known as CBF-1 in humans, Suppressor of hairless in Drosophila, Lag in Caenorhabditis elegans, and RBP-J in the mouse. Once bound to CSL, NICD recruits other coactivators including mastermind proteins (MAML1-3), which in turn recruit the MED8-mediator transcription activation complex in order to induce transcriptional expression of downstream target genes (Figure 2). Members of the Hairy enhancer of split (Hes) or Hairy related (Hey or Hrt) genes have been identified as Notch target genes in many tissues, while other targets are more tissue restricted. Recent studies via genome-wide expression and chromatin immunoprecipitation (ChIP) arrays point to the existence of a large number of genes that can be directly regulated by Notch (Palomero et al., 2006Palomero T. Lim W.K. Odom D.T. Sulis M.L. Real P.J. Margolin A. Barnes K.C. O'Neil J. Neuberg D. Weng A.P. et al.NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth.Proc. Natl. Acad. Sci. USA. 2006; 103: 18261-18266Crossref PubMed Scopus (288) Google Scholar, Weng et al., 2006Weng A.P. Millholland J.M. Yashiro-Ohtani Y. Arcangeli M.L. Lau A. Wai C. Del Bianco C. Rodriguez C.G. Sai H. Tobias J. et al.c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma.Genes Dev. 2006; 20: 2096-2109Crossref PubMed Scopus (325) Google Scholar). The challenge will now be to distinguish the drivers from the passengers among the large number of target genes. Moreover, there is emerging data suggesting that Notch can crosstalk to or cooperate with other signaling pathways (including NF-κB, hypoxia, or TGF-β) and thereby broaden the spectrum of target genes that are influenced by Notch signaling (Poellinger and Lendahl, 2008Poellinger L. Lendahl U. Modulating Notch signaling by pathway-intrinsic and pathway-extrinsic mechanisms.Curr. Opin. Genet. Dev. 2008; 18: 449-454Crossref PubMed Scopus (29) Google Scholar, Samon et al., 2008Samon J.B. Champhekar A. Minter L.M. Telfer J.C. Miele L. Fauq A. Das P. Golde T.E. Osborne B.A. Notch1 and TGFbeta1 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cells.Blood. 2008; 112: 1813-1821Crossref PubMed Scopus (69) Google Scholar). Notch signaling is regulated at multiple levels. For example, cell type-specific and spatial expression of ligands and Notch receptors can restrict signaling to a certain cell population or context. The ability of Jagged ligands to trigger Notch receptor-mediated signaling is dependent on the glycosylation status of the extracellular domain of Notch. Fringe proteins are glycosyl transferases that add N-Acetylglucosamine to O-fucose residues present within certain epidermal growth factor-like repeats of the receptors (Haines and Irvine, 2003Haines N. Irvine K.D. Glycosylation regulates Notch signalling.Nat. Rev. Mol. Cell Biol. 2003; 4: 786-797Crossref PubMed Scopus (322) Google Scholar). Notch receptors carrying these additional sugar moieties preferentially signal via Delta ligands, while Jagged-mediated Notch signaling is inhibited. Another level of regulation is to ensure that a Notch signal is short lived. Notch receptors carry a PEST domain at the very C terminus that is responsible for rapid turnover of the activated NICD via E3-ubiquitin ligase (including Fbw7)-mediated proteosomal degradation (Figure 2; O'Neil et al., 2007O'Neil J. Grim J. Strack P. Rao S. Tibbitts D. Winter C. Hardwick J. Welcker M. Meijerink J.P. Pieters R. et al.FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors.J. Exp. Med. 2007; 204: 1813-1824Crossref PubMed Scopus (223) Google Scholar, Thompson et al., 2007Thompson B.J. Buonamici S. Sulis M.L. Palomero T. Vilimas T. Basso G. Ferrando A. Aifantis I. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia.J. Exp. Med. 2007; 204: 1825-1835Crossref PubMed Scopus (175) Google Scholar). The blood system originates from different sites during embryonic development and is generally closely associated with vasculogenesis. The most primitive hematopoietic cells are found within the extraembryonic yolk sac before hematopoiesis shifts to intraembryonic sites including the para-aortic splanchnopleiura and aorta-gonad mesonephros (P-sP and AGM). Later hematopoiesis occurs in the fetal liver before it is finally established in the bone marrow (Godin and Cumano, 2002Godin I. Cumano A. The hare and the tortoise: An embryonic haematopoietic race.Nat. Rev. Immunol. 2002; 2: 593-604Crossref PubMed Google Scholar). The first hematopoietic stem cells capable of long-term repopulation of all blood lineages upon transplantation are found within the AGM region. These cells are generated from a bipotent hemangioblast by budding off from the dorsal aorta of midgestation embryos (de Bruijn et al., 2002de Bruijn M.F. Ma X. Robin C. Ottersbach K. Sanchez M.J. Dzierzak E. Hematopoietic stem cells localize to the endothelial cell layer in the midgestation mouse aorta.Immunity. 2002; 16: 673-683Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). Germline mutant embryos deficient for Notch1 or RBP-J have been shown not to generate intraembryonic HSCs, whereas yolk sac hematopoiesis of these mutant mice was unperturbed (Kumano et al., 2003Kumano K. Chiba S. Kunisato A. Sata M. Saito T. Nakagami-Yamaguchi E. Yamaguchi T. Masuda S. Shimizu K. Takahashi T. et al.Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells.Immunity. 2003; 18: 699-711Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, Robert-Moreno et al., 2005Robert-Moreno A. Espinosa L. de la Pompa J.L. Bigas A. RBPjkappa-dependent Notch function regulates Gata2 and is essential for the formation of intra-embryonic hematopoietic cells.Development. 2005; 132: 1117-1126Crossref PubMed Scopus (107) Google Scholar). These studies led to the suggestion that Notch signaling is important for definitive but not primitive hematopoiesis. However, Notch signaling is also important for arterial cell fate specification in developing blood vessels. Hence, these mutant embryos displayed severe vasculogenic defects characterized by the loss of arterial cell fate (Krebs et al., 2004Krebs L.T. Shutter J.R. Tanigaki K. Honjo T. Stark K.L. Gridley T. Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants.Genes Dev. 2004; 18: 2469-2473Crossref PubMed Scopus (264) Google Scholar). Therefore, it was not clear whether the inability to generate intraembryonic HSC is a cell-autonomous defect of hemangioblasts or simply a secondary effect resulting from the absence of arteries. This uncertainty was recently resolved by studies analyzing germline mutant mice for the Jagged ligand family. Jagged1 but not Jagged2 null embryos failed to generate hematopoietic cells in the AGM, without losing the arterial cell fate (Robert-Moreno et al., 2008Robert-Moreno A. Guiu J. Ruiz-Herguido C. López M.E. Inglés-Esteve J. Riera L. Tipping A. Enver T. Dzierzak E. Gridley T. et al.Impaired embryonic haematopoiesis yet normal arterial development in the absence of the Notch ligand Jagged1.EMBO J. 2008; 27: 1886-1895Crossref PubMed Scopus (60) Google Scholar). Moreover, the same study linked Jagged1-mediated Notch signaling to GATA2 and Runx1 expression, two important transcription factors for hematopoiesis. These observations were important because they were the first studies showing that Notch signaling is directly associated with the generation of hematopoietic cells independently of its role in arterial development. Thus, Notch signaling is indeed essential for definitive hematopoiesis in the developing embryo. Whether Notch signaling plays a similar role during the generation or maintenance of HSC in the adult bone marrow compartment was debated for several years. Jagged1 was suggested to be part of the HSC stem cell niche, because osteoblast-specific expression of the parathyroid hormone-related protein receptor (PTHRP) resulted in increased numbers of Jagged1-expressing osteoblasts, which correlated with increased numbers of HSCs. This result led to the suggestion that Jagged1-mediated Notch signaling might regulate HSC homeostasis (Calvi et al., 2003Calvi L.M. Adams G.B. Weibrecht K.W. Weber J.M. Olson D.P. Knight M.C. Martin R.P. Schipani E. Divieti P. Bringhurst F.R. et al.Osteoblastic cells regulate the haematopoietic stem cell niche.Nature. 2003; 425: 841-846Crossref PubMed Scopus (1618) Google Scholar). Moreover, multiple gain-of-function studies support a role for Notch in HSC maintenance. Overexpression of N1-ICD or its downstream target gene Hes1 in bone marrow progenitors resulted in increased HSC numbers and/or enhanced self-renewal (Kunisato et al., 2003Kunisato A. Chiba S. Nakagami-Yamaguchi E. Kumano K. Saito T. Masuda S. Yamaguchi T. Osawa M. Kageyama R. Nakauchi H. et al.HES-1 preserves purified hematopoietic stem cells ex vivo and accumulates side population cells in vivo.Blood. 2003; 101: 1777-1783Crossref PubMed Scopus (86) Google Scholar, Stier et al., 2002Stier S. Cheng T. Dombkowski D. Carlesso N. Scadden D.T. Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome.Blood. 2002; 99: 2369-2378Crossref PubMed Scopus (228) Google Scholar). Coculture experiments of murine hematopoietic progenitor cells with immobilized Notch ligands promoted early T cell differentiation and generation of multilog increases in the number of hematopoietic progenitor cells with short-term lymphoid and myeloid repopulating activity (Varnum-Finney et al., 2003Varnum-Finney B. Brashem-Stein C. Bernstein I.D. Combined effects of Notch signaling and cytokines induce a multiple log increase in precursors with lymphoid and myeloid reconstituting ability.Blood. 2003; 101: 1784-1789Crossref PubMed Scopus (135) Google Scholar). The dose of Notch signaling determines the in vitro process of hematopoietic progenitor cell expansion versus B and/or T cell differentiation. Coculture of hematopoietic progenitor cells in the presence of high densities of Notch ligands increases the propensity to drive differentiation toward the T cell lineage (Dallas et al., 2005Dallas M.H. Varnum-Finney B. Delaney C. Kato K. Bernstein I.D. Density of the Notch ligand Delta1 determines generation of B and T cell precursors from hematopoietic stem cells.J. Exp. Med. 2005; 201: 1361-1366Crossref PubMed Scopus (65) Google Scholar). In particular, the finding that human umbilical cord blood cells (UCB) could also be expanded ex vivo when cocultured with Delta-like1-IgG fusion proteins and that these cells showed a marked increase (approximately 15-fold) in repopulating cell frequency in xenotransplantation assays (Delaney et al., 2005Delaney C. Varnum-Finney B. Aoyama K. Brashem-Stein C. Bernstein I.D. Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells.Blood. 2005; 106: 2693-2699Crossref PubMed Scopus (126) Google Scholar) may be exploited for clinical purposes (Bernstein et al., 2008Bernstein I.D. Boyd R.L. van den Brink M.R. Clinical strategies to enhance posttransplant immune reconstitution.Biol. Blood Marrow Transplant. 2008; 14: 94-99Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). Although it is very encouraging that Notch ligands are currently used to expand murine and human hematopoietic progenitors, there is limited evidence that Notch can be used to expand long-term HSCs. Thus, the question remains whether this is a physiological role of Notch signaling. This has been addressed by analyzing several conditional gene-targeted mice for different components of the Notch pathway. Mice lacking Notch1 or Jagged1 or both did not reveal any defects in HSC maintenance or in the capacity to repopulate the hematopoietic compartment after transplantation (Mancini et al., 2005Mancini S.J. Mantei N. Dumortier A. Suter U. MacDonald H.R. Radtke F. Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation.Blood. 2005; 105: 2340-2342Crossref PubMed Scopus (144) Google Scholar, Radtke et al., 1999Radtke F. Wilson A. Stark G. Bauer M. van Meerwijk J. MacDonald H.R. Aguet M. Deficient T cell fate specification in mice with an induced inactivation of Notch1.Immunity. 1999; 10: 547-558Abstract Full Text Full Text PDF PubMed Scopus (802) Google Scholar). These results do not exclude the possibility that other Notch receptors or ligands might functionally compensate for the loss of Notch1 and/or Jagged1. Two complementary approaches were recently used to block canonical Notch signaling. The first used a dominant-negative form of the Mastermind-like protein, which inhibits the formation of a functional Notch transactivation complex in HSCs and bone marrow (BM) progenitors, whereas the second inactivated the Rbp-j gene within HSCs. These experimental approaches block Notch signaling independently of Notch receptor or ligand usage. Notch signaling-deprived progenitors did not reveal any HSC defects; they showed normal long-term reconstitution even in secondary competitive transplantation assays (Maillard et al., 2008Maillard I. Koch U. Dumortier A. Shestova O. Xu L. Sai H. Pross S.E. Aster J.C. Bhandoola A. Radtke F. Pear W.S. Canonical notch signaling is dispensable for the maintenance of adult hematopoietic stem cells.Cell Stem Cell. 2008; 2: 356-366Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). Taken together, these experiments show that canonical Notch signaling is dispensable for HSC homeostasis in the bone marrow. Moreover, the identification of the proto-oncogene LRF (Leukemia/lymphoma Related Factor, encoded by the Zbtb7a gene and also known as Pokemon) as a negative regulator of Notch signaling in BM progenitors indicates that Notch signaling must be repressed or under very stringent control in HSCs in order to prevent ectopic T cell differentiation in the BM (Maeda et al., 2007Maeda T. Merghoub T. Hobbs R.M. Dong L. Maeda M. Zakrzewski J. van den Brink M.R. Zelent A. Shigematsu H. Akashi K. et al.Regulation of B versus T lymphoid lineage fate decision by the proto-oncogene LRF.Science. 2007; 316: 860-866Crossref PubMed Scopus (104) Google Scholar). How LRF represses Notch signaling in HSC or progenitor cells is currently unknown. The essential role of Notch signaling during thymic T cell lineage commitment and maturation is the best-studied function of Notch in hematopoiesis. Via the blood stream, BM progenitors constantly seed the thymus, where they adopt a T cell fate and further differentiate into mature αβ and γδ T cells before emigrating to the periphery. Multiple genetic loss- and gain-of-function studies highlight the importance of Notch1 for T cell lineage commitment. Inducible inactivation of Notch1 or Rbp-j results in a block in T cell development accompanied by the accumulation of ectopic B cells in the thymus (Han et al., 2002Han H. Tanigaki K. Yamamoto N. Kuroda K. Yoshimoto M. Nakahata T. Ikuta K. Honjo T. Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision.Int. Immunol. 2002; 14: 637-645Crossref PubMed Google Scholar, Radtke et al., 1999Radtke F. Wilson A. Stark G. Bauer M. van Meerwijk J. MacDonald H.R. Aguet M. Deficient T cell fate specification in mice with an induced inactivation of Notch1.Immunity. 1999; 10: 547-558Abstract Full Text Full Text PDF PubMed Scopus (802) Google Scholar). These results were initially interpreted to mean that canonical Notch1 signaling instructs a bipotent early thymic progenitor to adopt a T cell as opposed to a B cell fate because no other myeloid or lymphoid lineages were affected. Nevertheless, recent loss of Notch1 function combined with lineage tracing experiments reveal that the inhibitory functions of Notch1 are broader. Notch1 inhibits multiple cell fate potentials of thymus-seeding cells including myeloid and B cells, as well as conventional and plasmacytoid dendritic cell potential (both in a cell-intrinsic and -extrinsic manner) and thereby ensures efficient T cell lineage commitment (Bell and Bhandoola, 2008Bell J.J. Bhandoola A. The earliest thymic progenitors for T cells possess myeloid lineage potential.Nature. 2008; 452: 764-767Crossref PubMed Scopus (188) Google Scholar, Feyerabend et al., 2009Feyerabend T.B. Terszowski G. Tietz A. Blum C. Luche H. Gossler A. Gale N.W. Radtke F. Fehling H.J. Rodewald H.-R. Deletion of Notch1 converts pro-T cells to dendritic cells and promotes thymic B cells by cell-extrinsic and cell-intrinsic mechanisms.Immunity. 2009; 30: 67-79Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, Wada et al., 2008Wada H. Masuda K. Satoh R. Kakugawa K. Ikawa T. Katsura Y. Kawamoto H. Adult T-cell progenitors retain myeloid potential.Nature. 2008; 452: 768-772Crossref PubMed Scopus (167) Google Scholar). Similarly, interference with Notch signaling by transgenic expression of Notch modulators (including Fringe, Deltex1, or Nrarp) or dominant-negative forms of the transcriptional coactivator MAML-1 also blocks T cell development concomitant with B lymphopoiesis in the thymus (Izon et al., 2002Izon D.J. Aster J.C. He Y. Weng A. Karnell F.G. Patriub V. Xu L. Bakkour S. Rodriguez C. Allman D. Pear W.S. Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1.Immunity. 2002; 16: 231-243Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar, Koch et al., 2001Koch U. Lacombe T.A. Holland D. Bowman J.L. Cohen B.L. Egan S.E. Guidos C.J. Subversion of the T/B lineage decision in the thymus by lunatic fringe-mediated inhibition of Notch-1.Immunity. 2001; 15: 225-236Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, Maillard et al., 2004Maillard I. Weng A.P. Carpenter A.C. Rodriguez C.G. Sai H. Xu L. Allman D. Aster J.C. Pear W.S. Mastermind critically regulates Notch-mediated lymphoid cell fate decisions.Blood. 2004; 104: 1696-1702Crossref PubMed Scopus (153) Google Scholar, Yun and Bevan, 2003Yun T.J. Bevan M.J. Notch-regulated ankyrin-repeat protein inhibits Notch1 signaling: multiple Notch1 signaling pathways involved in T cell development.J. Immunol. 2003; 170: 5834-5841PubMed Google Scholar). Reciprocal gain-of-function studies involving overexpressing N1-ICD in BM progenitors result in ectopic T cell development at the expense of B cell development in the BM (Pui et al., 1999Pui J.C. Allman D. Xu L. DeRocco S. Karnell F.G. Bakkour S. Lee J.Y. Kadesch T. Hardy R.R. Aster J.C. Pear W.S. Notch1 expression in early lymphopoiesis influences B versus T lineage determination.Immunity. 1999; 11: 299-308Abstract Full Text Full Text PDF PubMed Scopus (620) Google Scholar). Taken together, these results demonstrate that Notch1 is the key receptor expressed on thymus-seeding cells responsible for T cell lineage commitment. The question of the ligand(s) required for this process was recently addressed. Historically, Dll1 and somewhat later Dll4 have been favored as potential Notch1 ligands for T cell fate specification based on their capacity to support complete development of mature T cells from BM precursors in vitro (Hozumi et al., 2004Hozumi K. Negishi N. Suzuki D. Abe N. Sotomaru Y. Tamaoki N. Mailhos C. Ish-Horowicz D. Habu S. Owen M.J. Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo.Nat. Immunol. 2004; 5: 638-644Crossref PubMed Scopus (161) Google Scholar, Jaleco et al., 2001Jaleco A.C. Neves H. Hooijberg E. Gameiro P. Clode N. Haury M. Henrique D. Parreira L. Differential effects of Notch ligands Delta-1 and Jagged-1 in human lymphoid differentiation.J. Exp. Med. 2001; 194: 991-1002Crossref PubMed Scopus (215) Google Scholar, Schmitt and Zúñiga-Pflücker, 2002Schmitt T.M. Zúñiga-Pflücker J.C. Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro.Immunity. 2002; 17: 749-756Abstract Full Text Full Text PDF PubMed Scopus (563) Google Scholar). Nevertheless, inactivation of Dll4 but not Dll1 in thymic epithelial cells (TECs) resulted in a complete block in T cell development accompanied by ectopic B cell development within the thymus, which phenocopies mice with loss of Notch1 function in BM progenitors (Hozumi et al., 2008Hozumi K. Negishi N. Tsuchiya I. Abe N. Hirano K. Suzuki D. Yamamoto M. Engel J.D. Habu S. Notch signaling is necessary for GATA3 function in the initiation of T cell development.Eur. J. Immunol. 2008; 38: 977-985Crossref PubMed Scopus (15) Google Scholar, Koch et al., 2008Koch U. Fiorini E. Benedito R. Besseyrias V. Schuster-Gossler K. Pierres M. Manley N.R. Duarte A. Macdonald H.R. Radtke F. Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment.J. Exp. Med. 2008; 205: 2515-2523Crossref PubMed Scopus (127) Google Scholar). These results demonstrate an essential interaction between Dll4-expressing TECs and thymus-seeding Notch1-expressing hematopoietic progenitors for T lineage commitment. Previous studies of the thymic epithelium of gene-targeted mice in which T cell development is arrested at early developmental stages showed that the thymocyte progenitors also influence TEC maturation and function. Thus, lymphostromal interactions between developing thymocytes and TECs are bidirectional, a concept known as “thymus crosstalk” (van Ewijk et al., 1994van Ewijk W. Shores E.W. Singer A. Crosstalk in the mouse thymus.Immunol. Today. 1994; 15: 214-217Abstract Full Text PDF PubMed Scopus (138) Google Scholar). In this context, a recent report showed that maturation of thymocytes to the CD4+CD8+ stage induced downregulation of Dll4 on cortical TECs suggesting a negative-feedback loop between developing thymocytes and cortical TECs (Fiorini et al., 2008Fiorini E. Ferrero I. Merck E. Favre S. Pierres M. Luther S.A. MacDonald H.R. Cutting edge: Thymic crosstalk regulates delta-like 4 expression on cortical epithelial cells.J. Immunol. 2008; 181: 8199-8203Crossref PubMed Google Scholar). This coincides with the maturation and the ability of medullary TECs to mediate positive and negative selection, a trait that is acquired in a thymocyte-dependent manner (Alves et al., 2009Alves N.L. Huntington N.D. Rodewald H.R. Di Santo J.P. Thymic epithelial cells: the multi-tasking framework of the T cell “cradle”.Trends Immunol. 2009; 30: 468-474Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). How and whether downregulation of Dll4 on cortical TECs is essential to allow positive and/or negative selection remains an open question. Once the T cell lineage has been specified, developing thymocytes must choose between the αβ and γδ T cell lineage. γδ T cell development is mostly driven by the successful rearrangement of T cell receptor γ (TCR-γ) and TCR-δ genes and appears to be Notch independent (Ciofani et al., 2006Ciofani M. Knowles G.C. Wiest D.L. von Boehmer H. Zúñiga-Pflücker J.C. Stage-specific and differential notch dependency at the alphabeta and gammadelta T lineage bifurcation.Immunity. 2006; 25: 105-116Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, Wolfer et al., 2002Wolfer A. Wilson A. Nemir M. MacDonald H.R. Radtke F. Inactivation of Notch1 impairs VDJbeta rearrangement and allows pre-TCR-independent survival of early alpha beta lineage thymocytes.Immunity. 2002; 16: 869-879Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar). Interestingly, the helix-loop-helix protein Id3 can induce promotion of the γδ T cell fate as well as rendering γδ T cell maturation independent of Notch signaling (Lauritsen et al., 2009Lauritsen J.P. Wong G.W. Lee S.Y. Lefebvre J.M. Ciofani M. Rhodes M. Kappes D.J. Zúñiga-Pflücker J.C. Wiest D.L. Marked induction of the helix-loop-helix protein Id3 promotes the gammadelta T cell fate and renders their functional maturation Notch independent.Immunity. 2009; 31: 565-575Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar)" @default.
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• W1968627142 date "2010-01-01" @default.
• W1968627142 modified "2023-10-14" @default.
• W1968627142 title "Notch Signaling in the Immune System" @default.
• W1968627142 cites W1484840368 @default.
• W1968627142 cites W1487837935 @default.
• W1968627142 cites W1518341125 @default.
• W1968627142 cites W1522868374 @default.
• W1968627142 cites W1542406910 @default.
• W1968627142 cites W1572186962 @default.
• W1968627142 cites W1750541350 @default.
• W1968627142 cites W1871729829 @default.
• W1968627142 cites W1878384586 @default.
• W1968627142 cites W1891992064 @default.
• W1968627142 cites W1965543291 @default.
• W1968627142 cites W1966530387 @default.
• W1968627142 cites W1968343429 @default.
• W1968627142 cites W1969179523 @default.
• W1968627142 cites W1969261822 @default.
• W1968627142 cites W1977962361 @default.
• W1968627142 cites W1980212327 @default.
• W1968627142 cites W1980854526 @default.
• W1968627142 cites W1986884551 @default.
• W1968627142 cites W1986952411 @default.
• W1968627142 cites W1989024966 @default.
• W1968627142 cites W1990427876 @default.
• W1968627142 cites W1995421851 @default.
• W1968627142 cites W1995863606 @default.
• W1968627142 cites W1997516537 @default.
• W1968627142 cites W1997801717 @default.
• W1968627142 cites W1998662278 @default.
• W1968627142 cites W1999331935 @default.
• W1968627142 cites W2000589976 @default.
• W1968627142 cites W2002921066 @default.
• W1968627142 cites W2004045403 @default.
• W1968627142 cites W2005862926 @default.
• W1968627142 cites W2009163796 @default.
• W1968627142 cites W2010204335 @default.
• W1968627142 cites W2015026409 @default.
• W1968627142 cites W2017625115 @default.
• W1968627142 cites W2018527149 @default.
• W1968627142 cites W2024490058 @default.
• W1968627142 cites W2028735719 @default.
• W1968627142 cites W2032095580 @default.
• W1968627142 cites W2032951893 @default.
• W1968627142 cites W2035543586 @default.
• W1968627142 cites W2036385874 @default.
• W1968627142 cites W2038271225 @default.
• W1968627142 cites W2038661420 @default.
• W1968627142 cites W2039505162 @default.
• W1968627142 cites W2039971323 @default.
• W1968627142 cites W2041572974 @default.
• W1968627142 cites W2042666427 @default.
• W1968627142 cites W2042784167 @default.
• W1968627142 cites W2044766358 @default.
• W1968627142 cites W2046464033 @default.
• W1968627142 cites W2047137615 @default.
• W1968627142 cites W2047820200 @default.
• W1968627142 cites W2050700188 @default.
• W1968627142 cites W2051292725 @default.
• W1968627142 cites W2054302306 @default.
• W1968627142 cites W2056429839 @default.
• W1968627142 cites W2060710804 @default.
• W1968627142 cites W2061696866 @default.
• W1968627142 cites W2061996746 @default.
• W1968627142 cites W2066270106 @default.
• W1968627142 cites W2067131315 @default.
• W1968627142 cites W2070640889 @default.
• W1968627142 cites W2070793750 @default.
• W1968627142 cites W2071980761 @default.
• W1968627142 cites W2072956174 @default.
• W1968627142 cites W2075291089 @default.
• W1968627142 cites W2075317148 @default.
• W1968627142 cites W2075566981 @default.
• W1968627142 cites W2075904779 @default.
• W1968627142 cites W2076903534 @default.
• W1968627142 cites W2078497756 @default.
• W1968627142 cites W2079231292 @default.
• W1968627142 cites W2079762668 @default.
• W1968627142 cites W2082631225 @default.
• W1968627142 cites W2085948054 @default.
• W1968627142 cites W2086604490 @default.
• W1968627142 cites W2091129822 @default.
• W1968627142 cites W2091341060 @default.
• W1968627142 cites W2093518810 @default.
• W1968627142 cites W2095397411 @default.
• W1968627142 cites W2096015304 @default.
• W1968627142 cites W2099673075 @default.
• W1968627142 cites W2100979164 @default.
• W1968627142 cites W2106933841 @default.
• W1968627142 cites W2112622667 @default.
• W1968627142 cites W2114675972 @default.
• W1968627142 cites W2115181518 @default.
• W1968627142 cites W2116274406 @default.

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