Concise Review: Notch Signaling in Stem Cell Systems - 《stemcells》干细胞学杂志干细胞之家



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发表于 2009-3-4 23:59 |只看该作者 |倒序浏览 |打印

作者：Shigeru Chiba作者单位：Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo, Japan ! q0 K. {9 G$ k) R- x) E; T
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      【摘要】% E* O5 K3 o5 `: i3 g- I0 B
   The Notch signaling pathway is among the most commonly used communication channels in animal cells. Recent studies have demonstrated that this pathway is indispensable for cells in various stages of maturation, including terminal differentiation. One main focus in mammalian studies is the role of Notch in embryonic and postembryonic stem cell systems. In this review, the roles of Notch signaling in various mammalian stem and early progenitor cells are summarized.
      【关键词】 Stem cell Notch Embryogenesis Homeostasis# Q, a3 N( b- d# \7 _
   INTRODUCTION
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In mammals, a wide variety of cells use the Notch signaling system for embryonic development and, in adults, maintenance of homeostasis. A number of review articles have focused on the developmental biology . The present paper reviews the current knowledge of the roles of Notch signals in various stem and early progenitor cell systems in both the developmental and adult phases.; s5 U& j8 N2 B

HISTORICAL BACKGROUND OF NOTCH

The Notch gene was named for the phenotype of a mutant Drosophila with an indentation in the wings .
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Although such a concept was established in lower animals such as Drosophila and Caenorhabditis elegans, homologs in vertebrates were first found in Xenopus . It is now known that the Notch signaling pathway also influences cell fate decisions in mammals, such as cell differentiation, survival/apoptosis, and cell cycle in both physiologic and pathologic contexts, particularly in conjunction with stem cell behavior.9 B2 n2 m: J/ e/ P4 p

NOTCH SIGNALING PATHWAY AND ITS COMPONENTS1 I  C" z2 N. v$ X- d9 ]
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In mammals, four Notch receptors (Notch1¨CNotch4) and five structurally similar Notch ligands (Delta-like1  (Fig. 1).

Figure 1. Protein structure of Notch receptors and their ligands. There are 36 EGF-like repeats in Notch1 and Notch2, 34 repeats in Notch3, and 29 repeats in Notch4. Some of the EGF-like repeats serve as a ligand-binding site. LNR has inhibitory function against the cleavage. HDs in the extracellular subunit and transmembrane subunit consist of 103 and 65 amino acids, respectively. RAM associates with CSL protein. ANK associates with proteins to form a complex. PEST negatively regulates the half-life of Notch proteins. DSL is a binding site for Notch. Abbreviations: ANK, ankyrin repeat; CR, cysteine-rich repeat; DSL, Delta-Serrate-Lag2 domain; EGF, epidermal growth factor; HD, heterodimerization domain; LNR, Lin-Notch repeat; NLS, nuclear localization signal; PEST, PEST domain; PM, plasma membrane; RAM, ram domain; TAD, transactivation domain.

Under physiologic conditions, the ligand expressed on one cell binds to a Notch receptor expressed on neighboring cells that are in direct contact. Binding triggers the cleavage of the extracellular region of the Notch transmembrane subunit (S2 cleavage) ; this RIP might be related to the Notch signaling pathway. A number of Notch signal-modifying proteins have been identified, and the presence of noncanonical, CSL-independent pathways has been advocated, which are not included in this review.
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NOTCH SIGNALING IN STEM CELLS DURING EMBRYONIC DEVELOPMENT5 P' v8 z! G* l; h0 y' L
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During embryogenesis, it is not always easy to distinguish between primordial cells and tissue-specific stem cells and between stem cells and progenitors. Therefore, stem cells are most broadly considered in this section. Studies using gene-modified animals, which have demonstrated roles of Notch signaling in stem and early progenitor cells, are summarized in Table 1.' O/ R7 ~* a7 d

Table 1. Gene-modified animal studies demonstrating roles of Notch signaling in stem and early progenitor cells& K/ N# G- ]5 H* r; ?& \
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Phenotypes of Mice with Mutated Notch and Ligand Genes and Their Roles in Embryogenesis
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Mutations have been introduced in mice for each of the four Notch genes (Notch1¨CNotch4) and four Notch ligand genes (Delta-like1, Delta-like4, Jagged1, and Jagged2). Mice, homozygously disrupted with either Notch1 . These findings indicate that most of the individual Notch genes and ligand genes have nonredundant roles in mouse embryogenesis. Somitogenesis, abnormal vasculature formation, increased cellular apoptosis, excessive neuronal differentiation, etc., are observed in these mutant mice. There are, however, both similar and dissimilar phenotypes in these mice, and the causes of fatality in early to midgestation stages are not likely to be uniform in the knockout mice for each gene.

On the other hand, successful progression to midgestation stages implies that Notch signaling is unnecessary for the very early stage of embryogenesis, including the fertilized egg stage .9 E1 R9 f" A. ]% M

Roles in the Central Nervous System During Embryogenesis5 V* D8 c* P/ E+ h. l3 `, \
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Among undifferentiated neuroectodermal cells with the same potential during Drosophila embryogenesis, some cells will eventually express Delta at higher levels, which sends a signal to surrounding cells that uniformly express the Notch receptor. Cells receiving the signal are blocked from differentiating to neuroglioblasts (NGBs) and eventually assume another differentiation fate. On the other hand, cells that express Delta differentiate to NGBs and subsequently to neurons and glial cells . Accordingly, insufficient levels of Notch signals result in the "neurogenic phenotype," in which all cells with neuronal potential differentiate into neurons.; W0 n  _1 C) O% Q) Z. l
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Precocious neuronal differentiation observed in Notch pathway-deficient neurocompetent cells is also detected in mammals, such as in mice with inactivated Notch1 .

Importantly, Notch signaling either promotes or, by default, facilitates glial cell fate, perhaps as a consequence of inhibiting neuronal cell fate . These concepts fit the conventional view of the fundamental function of Notch signaling to prevent cells from taking the first pathway while guiding them into a secondary pathway.
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To add to the complexity, neural stem cells have been identified in glial cell populations, particularly in astrocytes . It remains to be clarified how Notch signaling is involved specifically in the maintenance of stem cell characteristics and the promotion of glial differentiation.

Notch signaling is also involved in the regulation of apoptosis in mammals. It remains controversial, however, whether it is pro- or antiapoptotic in developing neural stem/progenitor cells. Conditional deletion of Notch1 . Thus, the regulation of apoptosis and survival by Notch signaling must be highly context-dependent, and reciprocal directions should be considered on this axis for understanding the development of neural stem/progenitor cells.

Roles in Generating Hematopoietic Stem Cells

In mice, phenotypically defined endothelial cells that possess hematopoietic potential, called "hematogenic endothelial cells," are generated by E9.5 at the paraaorta-splanchnopleura (P-Sp) region. On E10.5, when the P-Sp develops to become the aorta-gonad-mesonephros (AGM), hematogenic endothelial cells develop into hematopoietic stem cells that have the potential to engraft in adult mouse bone marrow  produced similar results, indicating that Notch1 has an indispensable role at the point right before hematopoietic stem cells are generated.
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On the other hand, Notch1 is dispensable for primitive hematopoiesis and secondary hematopoiesis that is derived from progenitors, not from HSCs, in the yolk sac. Thus the requirement of Notch signaling during hematogenesis is most prominent in adult-type HSC generation .
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Role in Melanoblast Survival) v+ M0 N9 C6 i+ I

In embryonic skin, melanoblasts (Mbs) develop in the suprabasal and basal layers of the epidermis. The cleaved form of Notch1 is detected and the HES1 promoter is activated in the embryonic Mbs. A -secretase inhibitor induces apoptosis of embryonic Mbs, and tyrosinase promoter-dependent deletion of the rbpsuh gene results in severe coat color dilution in the initial hair . These results indicate that the embryonic Mbs use the Notch1-CSL-Hes1 pathway to protect themselves from apoptosis.

Roles in Vasculature Formation
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Mice with disrupted Notch-related molecules display various abnormalities in blood vessel formation, such as proliferation and migration of endothelial cells, smooth muscle differentiation, vascular remodeling processes  ligands in vasculature formation.' F( A8 A- U0 Z, M% S; H9 ^0 X

In the vascular system, Hey1, Hey2, and HeyL are considered candidate Notch-CSL targets .
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It has been proposed that the default pathway of the endothelial cells is "venous fate" and that Notch signaling instructively modulates endothelial cell fate to the "arterial fate" . In any case, it is clear that the Notch pathway is a critical determinant for arterial-venous endothelial cell fate., P7 x3 w' Y9 t" f' C8 s

Gain-of-function and loss-of-function experiments in vascular development sometimes yield similar results .! j2 d% G$ ~) I$ D  m

Roles in Organogenesis
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Analyses of Notch gene knockout mice and identification of Jagged1 as a responsible gene for a hereditary disease that accompanies defects in organ morphogenesis provide evidence that Notch signaling has important roles in the development of kidney, liver, pancreas, heart, etc.1 W6 K& Y/ J7 q, ^4 [( @

Notch2-null mouse embryos die before mesonephros generation .( J# w  Z9 w; C5 J7 _  Y$ Q

Alagille syndrome is an autosomal-dominant human disorder characterized by intrahepatic cholestasis; abnormalities of heart, eyes, and vertebrae; and a peculiar facial appearance. Haploinsufficiency of Jagged1 is responsible for this disorder  are similar to that of Alagille syndrome.

In the pancreas of Delta-like1 or rbpsuh gene knockout mice, there is an excess of endocrine cells , suggesting that Notch signaling physiologically inhibits pancreatic differentiation from bile epithelial cells, which have the potential to take the pancreatic cell fate in the absence of Notch signaling.
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The same mice exhibit excess differentiation to secretory cells, such as Goblet cells, in the intestinal mucosa at the expense of enterocytes . These findings together suggest a role of Notch signaling in the developing intestinal epithelium to regulate specification of the intestinal progenitor cells.! v& B! ?& X/ `8 X$ L4 t1 |1 E

Cell Fate Determination by Notch Signaling During Embryogenesis
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The above observations indicate that from the viewpoint of cell differentiation, Notch signaling has three major roles during embryonic development. First, it affects differentiation from primordial cells to tissue-specific stem cells in the early- to midstage embryo. In the traditional view of Drosophila nervous system development, differentiation from undifferentiated neuroectodermal cells to NGBs is inhibited. In mammals, however, induction rather than inhibition is postulated for HSC generation from upstream progenitors. The effect of Notch signaling on differentiation fate from primordial cells to tissue-specific stem cells might be context-dependent. Second, it inhibits tissue- or organ-specific stem cells or immature progenitors from further differentiation and presumably helps them expand while maintaining the immature state. Third, it blocks the default pathway and promotes the alternative pathway, which is typically observed during mid- to late-stage embryo development, such as during organ formation (Fig. 2).
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Figure 2. Influence of Notch signaling on the fate of stem and progenitor cells. The biologic effects of Notch signaling can be generalized as depicted in this figure. Notch signaling guides cells to differentiate or not and to differentiate to A instead of B or to B instead of A. Thus, Notch signaling has a role in increasing the number of stem or early progenitor cells.0 R; S7 m9 w. H
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ROLES OF NOTCH SIGNALING IN STEM CELLS POSTDEVELOPMENT

Adult stem cells are considered to maintain homeostasis of cells and tissues throughout life. The adult stem cells maintain the number of stem cells, as well as terminally differentiated cells, during normal turnover and repair damage after injury. Involvement of Notch signaling occurs during both normal status and injury in various stem cell systems. Studies along this line using gene-modified animals are summarized in Table 1.

Roles in the Skin
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Involvement of Notch signaling in postdevelopmental stem cell systems is best understood in the skin, particularly in the hair follicles. Notch1, Notch2, and Notch3 are expressed and differentially localized to various layers of the hair follicle .0 t+ w) g8 \( Q1 q8 ~! `
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After birth, the first hair cycle of Notch1-null mice shows a shortened anagen phase and premature entry into the catagen phase, and inactivation of Notch1 in adult mice results in almost complete hair loss followed by cyst formation. These observations indicate that Notch1 is essential for postnatal hair follicle development and homeostasis .8 n2 r8 x  i, ~8 [- I3 [

Notch overactivity in hair follicle cells also leads to abnormal hair formation . Thus, it is noteworthy that both loss and gain of Notch signaling similarly result in hyperkeratosis and hair loss due to hair cycle disturbances.

Analysis of mice with a specific deletion of rbpsuh in the skin using a nestin promoter-controlled Cre-lox system reveals that Notch signaling inhibits stem cells in the bulge, the stem cell niche in the hair follicle, from differentiating into epidermal cells and promotes hair formation .7 I  @7 u  U* \6 W
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In summary, Notch signals are likely to promote the selection of hair formation in bulge stem cells. Thus, ex vivo expansion of hair stem cells with the use of an artificial stem cell niche could revolutionize the dermatology/cosmetology field. Notch signaling should be an important component of such an artificial niche for hair stem cells. Moreover, the regulation of Notch signaling might be considered as a means for skin surface management.
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Roles in Hematopoietic and Immune Systems

In the hematopoietic and immune systems, Notch1, Notch2, and Notch3 are expressed in immature, as well as mature, blood cells and lymphocytes. Notch ligands are mainly expressed in the stromal cells and antigen-presenting cells, yet subsets of hematolymphopoietic cells also express some Notch ligands . Whether this signaling pathway is involved in HSC maintenance in the bone marrow niche and whether ex vivo HSC expansion is feasible using Notch signaling activators are issues that remain to be examined.
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HSC Maintenance in Adult Bone Marrow. Osteoblasts on the surfaces of trabecular bone have been identified as one of the bone marrow HSC niches .

Taken together, interactions between osteoblast-expressed Notch ligands such as Jagged1 and signal transmission to the Notch receptor-expressing HSCs might be one of the molecular mechanisms underlying the regulation of HSC in the osteoblastic niche in the bone marrow. The conditional deletion of both Notch1 and Jagged1, however, fails to show a clear-cut role for the Jagged1-Notch1 pathway in HSC maintenance . Therefore, truly convincing evidence must be demonstrated before we can draw conclusions about the physiologic role of Notch signaling for HSC maintenance in the bone marrow niche, including the osteoblastic and sinusoidal endothelial niches.) L4 [% K2 V. _6 G: q/ d
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Ex Vivo Expansion of HSCs Using Notch Signaling. Ex vivo expansion of HSCs maintained in the immature state has long attracted interest because of the potential utilization of expanded HSCs for transplantation, gene therapy, etc. . These findings raise the possibility of the clinical use of these proteins. To date, however, the degrees of SRC expansion have not been robust enough to establish clinically applicable ex vivo HSC expansion methods, although expansion of progenitors has been demonstrated to be more massive.
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Table 2. Effects of Notch ligands on murine and human hematopoietic stem/progenitor cells in culture
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A recent work by Delaney et al. indicates that low doses of immobilized Dll1-Fc are required for SRC expansion, whereas higher doses induce apoptosis of the cord blood-derived immature cells . In addition, it appears that there are differences in the biologic effects of diverse Notch ligands if they are used ex vivo. These issues raise another possibility that the bone marrow microenvironment can be better mimicked if we learn more about the biologic outcomes of diverse levels of Notch signaling or Notch signaling by different ligands.& j, G; [0 p! c( c
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Effects of Notch Signaling on Early Lymphopoietic Cells. Several important conclusions have been drawn from hematolymphopoietic cells differentiated from HSCs, such as that Notch signaling guides further differentiation of HSC-derived hematolymphopoietic cells, for example: (a) T and B lineage determination (in the progenitor stage between the HSCs and the most early thymocytes, Notch signaling blocks B lineage differentiation and promotes T-lineage differentiation) .

Information regarding the involvement of Notch signaling in the immune system is accumulating rapidly, and a comprehensive discussion of this topic is beyond the scope of this review. A number of review papers summarize the influence of Notch signals on lymphocyte development, particularly on T-cell development in the thymus .
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Roles in Intestinal Mucosal Cells
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Intestinal epithelial stem/progenitor cells are localized in the basal area of the crypts and continuously supply multiple types of mature cells .

The administration of -secretase inhibitors induces gross histologic changes in the intestinal epithelial layer of mice, such as an increased number of Goblet cells, endocrine cells, and abnormal crypts  and suggest that Notch signaling in adults functions to maintain intestinal epithelial stem/progenitor cells.7 J; o6 a, c, P4 c' x: _! g
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Roles in Skeletal Muscle Regeneration- R! X9 Z0 z  A% U" P

Satellite cells are stem cells of skeletal muscle fibers . Thus, Notch signaling is a key determinant of the muscle regenerative potential that declines with age.7 N. @9 }. w% q0 C- Y) I+ j
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CONCLUSION, K5 d$ z0 `1 |. H+ c1 n5 j% Q5 K1 `
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This report reviews the current knowledge of the Notch signaling pathway in various types of stem and early progenitor cells, but not germ cells. Ex vivo stem cell expansion is fundamental to the success of stem cell-based regeneration medicine, and it is likely that Notch signaling has a role in stem cell expansion. The effects of Notch signaling on progenitor cell survival have been demonstrated, and tumorigenic aspects must be considered.
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DISCLOSURES
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The author indicates no potential conflicts of interest.
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ACKNOWLEDGMENTS3 `5 e5 @) i2 W& k' Q
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I thank Raphael Kopan of Washington University (St. Louis) for the critical reading of this report and Keiki Kumano and Takahiro Suzuki of the University of Tokyo for useful discussion. This work was supported by Health and Labor Sciences Research grants (Research on Regulatory Science of Pharmaceuticals and Medical Devices) from the Ministry of Health, Labor and Welfare of Japan.
      【参考文献】
8 k; S/ W: @; N6 t: s( U& E5 N

Gridley T. Notch signaling and inherited disease syndromes. Hum Mol Genet 2003;12:R9¨CR13.
/ k! M. V* F- l6 V3 d% X
Iso T, Hamamori Y, Kedes L. Notch signaling in vascular development. Arterioscler Thromb Vasc Biol 2003;23:543¨C553.

Lefort K, Dotto GP. Notch signaling in the integrated control of keratinocyte growth/differentiation and tumor suppression. Semin Cancer Biol 2004;14:374¨C386.  n) ]* N3 V8 g1 v
" [6 G* L3 D1 \1 O* d0 A
Radtke F, Wilson A, Mancini SJ. Notch regulation of lymphocyte development and function. Nat Immunol 2004;5:247¨C253.8 @4 c2 r% t( h  a6 R  k' I' b

Suzuki T, Chiba S. Notch signaling in hematopoietic stem cells. Int J Hematol 2005;82:285¨C294.
4 [# `* v5 O* B# Z' u( g
Yoon K, Gaiano N. Notch signaling in the mammalian central nervous system: Insights from mouse mutants. Nat Neurosci 2005;8:709¨C715.

Maillard I, Fang T, Pear WS. Regulation of lymphoid development, differentiation, and function by the Notch pathway. Annu Rev Immunol 2005;23:945¨C974.
6 M3 G0 ]$ P( X: T! R+ {5 s
Baron M. An overview of the Notch signalling pathway. Semin Cell Dev Biol 2003;14:113¨C119.
8 ~1 T, `, O& {5 `+ o
Iso T, Kedes L, Hamamori Y. HES and HERP families: Multiple effectors of the Notch signaling pathway. J Cell Physiol 2003;194:237¨C255.

Le Borgne R, Schweisguth F. Notch signaling: Endocytosis makes delta signal better. Curr Biol 2003;13:R273¨CR275.. i" |% Z. a- q  H1 U( ~

Molofsky AV, Pardal R, Morrison SJ. Diverse mechanisms regulate stem cell self-renewal. Curr Opin Cell Biol 2004;16:700¨C707.1 x9 I8 l7 ]" d: Z

Mohr OL. Character changes caused by mutation of an entire region of a chromosome in Drosophila. Genetics 1919;4:275¨C282.

Poulson DF. The effects of certain X-chromosome deficiencies on the embryonic development of Drosophila melanogaster. J Exp Zool 1940;83:271¨C325.- X8 a4 F7 A/ ~) l8 x' D# U/ I3 u# S

Wharton KA, Johansen KM, Xu T. Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 1985;43:567¨C581.; E+ s- x# G8 U3 d* Y
( {0 t# M* E  Q9 B
Fehon RG, Kooh PJ, Rebay I. Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila. Cell 1990;61:523¨C534.0 I) p/ R+ f2 x1 q3 O. I

Sternberg PW. Lateral inhibition during vulval induction in Caenorhabditis elegans. Nature 1988;335:551¨C554.
* D& P: p5 E" y% k: |
Greenwald I, Rubin GM. Making a difference: The role of cell-cell interactions in establishing separate identities for equivalent cells. Cell 1992;68:271¨C281.  d* l( K1 y0 b6 J6 S  G
7 P! _& \# x( ^' X! c
Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science 1995;268:225¨C232.
0 M! Y9 H* ], ]4 V. b  d
Coffman C, Harris W, Kintner C. Xotch, the Xenopus homolog of Drosophila notch. Science 1990;249:1438¨C1441.

Ellisen LW, Bird J, West DC et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 1991;66:649¨C661.1 W: I  }, @6 y

Jarriault S, Brou C, Logeat F et al. Signalling downstream of activated mammalian Notch. Nature 1995;377:355¨C358.# {; O# U4 e$ _8 Q
! x' k' D& B4 m
Milner LA, Bigas A, Kopan R. Inhibition of granulocytic differentiation by mNotch1. Proc Natl Acad Sci U S A 1996;93:13014¨C13019." {3 W; Q8 Y$ V' s  [$ m
2 \/ Y2 ~8 F  d
Ladi E, Nichols JT, Ge W et al. The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. J Cell Biol 2005;170:983¨C992.
+ f- [6 Y/ C' `
Blaumueller CM, Qi H, Zagouras P et al. Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane. Cell 1997;90:281¨C291.

Logeat F, Bessia C, Brou C et al. The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci U S A 1998;95:8108¨C8112.

Brou C, Logeat F, Gupta N et al. A novel proteolytic cleavage involved in Notch signaling: The role of the disintegrin-metalloprotease TACE. Mol Cell 2000;5:207¨C216.

Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 1998;393:382¨C386.

Lai EC. Keeping a good pathway down: Transcriptional repression of Notch pathway target genes by CSL proteins. EMBO Rep 2002;3:840¨C845.
* x7 f( W: g  t' ^
Wu L, Aster JC, Blacklow SC et al. MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat Genet 2000;26:484¨C489.) c. z, f5 f, C' ^% P
0 T) Y! L; @% O5 B( N4 ?: ^
Kitagawa M, Oyama T, Kawashima T et al. A human protein with sequence similarity to Drosophila mastermind coordinates the nuclear form of notch and a CSL protein to build a transcriptional activator complex on target promoters. Mol Cell Biol 2001;21:4337¨C4346.9 Q' I0 Q) C/ K1 R% l" Q

Kageyama R, Ohtsuka T, Hatakeyama J. Roles of bHLH genes in neural stem cell differentiation. Exp Cell Res 2005;306:343¨C348." m4 t6 C' H* w. W* o1 ~0 v
& M; u/ J' W2 A& c1 d) k  h4 u
Okochi M, Steiner H, Fukumori A et al. Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1. EMBO J 2002;21:5408¨C5416.
" u+ P/ i. K( Y% g  V( \
Okochi M, Fukumori A, Jiang J et al. Secretion of the Notch-1 Abeta-like peptide during Notch signaling. J Biol Chem 2006;281:7890¨C7898.6 G& r8 p. P' d6 f( J

Swiatek PJ, Lindsell CE, del Amo FF et al. Notch1 is essential for postimplantation development in mice. Genes Dev 1994;8:707¨C719.8 ?/ ?6 T9 E  K3 _1 ?4 }9 v! {! h5 K

Conlon RA, Reaume AG, Rossant J. Notch1 is required for the coordinate segmentation of somites. Development 1995;121:1533¨C1545.
$ q7 b1 Q! J& J8 O1 L5 u
Hamada Y, Kadokawa Y, Okabe M et al. Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality. Development 1999;126:3415¨C3424.+ o" c4 ^; `; L* i  y5 t& t& y

Krebs LT, Xue Y, Norton CR et al. Characterization of Notch3-deficient mice: Normal embryonic development and absence of genetic interactions with a Notch1 mutation. Genesis 2003;37:139¨C143.) _6 m1 ?6 M  r% `4 ]
& r. u& j6 e8 L2 x6 V4 o
Krebs LT, Xue Y, Norton CR et al. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev 2000;14:1343¨C1352.
2 C. b6 Q$ w- \6 |. G- Y- G8 b
Domenga V, Fardoux P, Lacombe P et al. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev 2004;18:2730¨C2735.. s2 x& \3 o" y) i9 m' v5 j) D
4 E( g0 K0 b7 l( O6 L2 t
Hrabe de Angelis M, McIntyre J 2nd, Gossler A. Maintenance of somite borders in mice requires the Delta homologue DII1. Nature 1997;386:717¨C721.
' A1 E2 j9 T( A5 p1 d
Duarte A, Hirashima M, Benedito R et al. Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev 2004;18:2474¨C2478., g; f- [4 Q6 d0 g, X2 X
7 {  y- O8 c  y% T  M
Gale NW, Dominguez MG, Noguera I et al. Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Natl Acad Sci U S A 2004;101:15949¨C15954.

Xue Y, Gao X, Lindsell CE et al. Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet 1999;8:723¨C730.+ e7 d. s1 t& ~  g& M  ]
# b) u( z3 \+ N. i$ m  R$ [
Jiang R, Lan Y, Chapman HD et al. Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice. Genes Dev 1998;12:1046¨C1057.  G& F# w+ G% K: e  C; D4 u- D
5 V% o9 Y& O/ D8 B. \
Shi S, Stahl M, Lu L et al. Canonical Notch signaling is dispensable for early cell fate specifications in mammals. Mol Cell Biol 2005;25:9503¨C9508.
. F% H* s; M* M# C6 V
Schmitt TM, de Pooter RF, Gronski MA et al. Induction of T cell development and establishment of T cell competence from embryonic stem cells differentiated in vitro. Nat Immunol 2004;5:410¨C417.

Gaiano N, Fishell G. The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci 2002;25:471¨C490.6 f/ u' U* j% v2 |, K, W# u- y& j

de la Pompa JL, Wakeham A, Correia KM et al. Conservation of the Notch signalling pathway in mammalian neurogenesis. Development 1997;124:1139¨C1148.: Z" s' N+ |7 `1 N) |. k& A8 C2 C
; p. G0 F- H8 b$ E0 a) @
Lutolf S, Radtke F, Aguet M et al. Notch1 is required for neuronal and glial differentiation in the cerebellum. Development 2002;129:373¨C385.
' v: i' i) B* T1 D; x
Hitoshi S, Alexson T, Tropepe V et al. Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev 2002;16:846¨C858.

Ishibashi M, Ang SL, Shiota K et al. Targeted disruption of mammalian hairy and Enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural tube defects. Genes Dev 1995;9:3136¨C3148.! r! I4 Z7 S) C8 ^% a
" h2 ~5 A9 i/ W9 d* V& `$ B- \4 `
Ohtsuka T, Ishibashi M, Gradwohl G et al. Hes1 and Hes5 as notch effectors in mammalian neuronal differentiation. EMBO J 1999;18:2196¨C2207.5 g1 q5 y5 K$ H. w! O  y( Y

Hatakeyama J, Bessho Y, Katoh K et al. Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development 2004;131:5539¨C5550.

Ohtsuka T, Sakamoto M, Guillemot F et al. Roles of the basic helix-loop-helix genes Hes1 and Hes5 in expansion of neural stem cells of the developing brain. J Biol Chem 2001;276:30467¨C30474.

Gaiano N, Nye JS, Fishell G. Radial glial identity is promoted by Notch1 signaling in the murine forebrain. Neuron 2000;26:395¨C404.& v: l6 r4 |- y

Furukawa T, Mukherjee S, Bao ZZ et al. rax, Hes1, and notch1 promote the formation of Muller glia by postnatal retinal progenitor cells. Neuron 2000;26:383¨C394.' B2 ]& u8 W5 d
- a7 T. Q4 P: ]' p
Hojo M, Ohtsuka T, Hashimoto N et al. Glial cell fate specification modulated by the bHLH gene Hes5 in mouse retina. Development 2000;127:2515¨C2522.

Morrison SJ, Perez SE, Qiao Z et al. Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell 2000;101:499¨C510.

Lundkvist J, Lendahl U. Notch and the birth of glial cells. Trends Neurosci 2001;24:492¨C494.6 R! \6 \( d! r& _8 _! A( D- J
5 h1 R2 a' C  D6 N# p8 m
Tanigaki K, Nogaki F, Takahashi J et al. Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate. Neuron 2001;29:45¨C55.( D) r4 M# b+ R/ J3 R
1 H1 p3 K7 _% @4 }
Grandbarbe L, Bouissac J, Rand M et al. Delta-Notch signaling controls the generation of neurons/glia from neural stem cells in a stepwise process. Development 2003;130:1391¨C1402.5 W) ~4 q8 q& `2 c( O$ B& R/ F6 i

Mason JL, Jones JJ, Taniike M et al. Mature oligodendrocyte apoptosis precedes IGF-1 production and oligodendrocyte progenitor accumulation and differentiation during demyelination/remyelination. J Neurosci Res 2000;61:251¨C262.+ }/ W7 a2 L3 z5 v
# E) M/ o6 H4 {6 J2 R
Yang X, Klein R, Tian X et al. Notch activation induces apoptosis in neural progenitor cells through a p53-dependent pathway. Dev Biol 2004;269:81¨C94.; Q- x5 b4 Y* J; K! H

Devgan V, Mammucari C, Millar SE et al. p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation. Genes Dev 2005;19:1485¨C1495.: O" ?6 E9 p# D. M: g6 f

Noseda M, Chang L, McLean G et al. Notch activation induces endothelial cell cycle arrest and participates in contact inhibition: Role of p21Cip1 repression. Mol Cell Biol 2004;24:8813¨C8822.# w/ \* c- ?1 }% I7 B
+ t- f% C9 M4 D% R8 L8 h
Liu ZJ, Xiao M, Balint K et al. Inhibition of endothelial cell proliferation by Notch1 signaling is mediated by repressing MAPK and PI3K/Akt pathways and requires MAML1. FASEB J 2006;.& ]) O& Y! C& O1 V; s0 j! k8 g

Kang DE, Yoon IS, Repetto E et al. Presenilins mediate phosphatidylinositol 3-kinase/AKT and ERK activation via select signaling receptors. Selectivity of PS2 in platelet-derived growth factor signaling. J Biol Chem 2005;280:31537¨C31547.- e. F  S+ z( R% X: i. M
; }5 [$ S7 S' A3 S
Mungamuri SK, Yang X, Thor AD et al. Survival signaling by Notch1: Mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res 2006;66:4715¨C4724.# G/ g, S, b9 k5 a5 q
3 \* F& [3 G% q$ |
Dzierzak E. Ontogenic emergence of definitive hematopoietic stem cells. Curr Opin Hematol 2003;10:229¨C234.

Kumano K, Chiba S, Kunisato A et al. Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells. Immunity 2003;18:699¨C711.

Hadland BK, Huppert SS, Kanungo J et al. A requirement for Notch1 distinguishes 2 phases of definitive hematopoiesis during development. Blood 2004;104:3097¨C3105.8 X6 y% o0 r% Q) q* L7 B; `
) ~, U+ o) i3 x
Robert-Moreno A, Espinosa L, de la Pompa JL et al. RBPjkappa-dependent Notch function regulates Gata2 and is essential for the formation of intra-embryonic hematopoietic cells. Development 2005;132:1117¨C1126.

Moriyama M, Osawa M, Mak SS et al. Notch signaling via Hes1 transcription factor maintains survival of melanocytes and melanocyte stem cells. J Cell Biol 2006;173:333¨C339.
- q) D4 q8 P% O- c% Z- E: V
Krebs LT, Shutter JR, Tanigaki K et al. Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev 2004;18:2469¨C2473.

You LR, Lin FJ, Lee CT et al. Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature 2005;435:98¨C104.: S" u4 H: `8 G+ R: |$ i! O  D! c
# k% s& ]. q9 [* f  g; g( v5 d
Fischer A, Schumacher N, Maier M et al. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev 2004;18:901¨C911.0 t; m5 C# _0 T+ y2 `5 y% }

Lawson ND, Weinstein BM. Arteries and veins: Making a difference with zebrafish. Nat Rev Genet 2002;3:674¨C682.

Rossant J, Hirashima M. Vascular development and patterning: Making the right choices. Curr Opin Genet Dev 2003;13:408¨C412.( n1 R$ ^1 |$ O4 d& r2 N5 b4 O
, |7 C, y3 I* J) n/ ?. ]
Zhong TP, Childs S, Leu JP et al. Gridlock signalling pathway fashions the first embryonic artery. Nature 2001;414:216¨C220.

Thurston G, Yancopoulos GD. Gridlock in the blood. Nature 2001;414:163¨C164.

Uyttendaele H, Ho J, Rossant J et al. Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium. Proc Natl Acad Sci U S A 2001;98:5643¨C5648.1 F% z3 _4 I5 D* v$ {
$ M1 A, T3 Q% Z$ _2 C' I
McCright B, Gao X, Shen L et al. Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation. Development 2001;128:491¨C502.0 D* v5 f1 p6 G* y% B: d, \  h( R& P: ~
2 p' R" b; l: h, W# L. s4 L/ P6 L
Oda T, Elkahloun AG, Pike BL et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 1997;16:235¨C242.4 A5 p+ g" _0 A

Li L, Krantz ID, Deng Y et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 1997;16:243¨C251.% V8 H& ^) `2 n, h' u

Suzuki A, Zheng YW, Kaneko S et al. Clonal identification and characterization of self-renewing pluripotent stem cells in the developing liver. J Cell Biol 2002;156:173¨C184.* S" u. [: ]/ h: N# A

Apelqvist A, Li H, Sommer L et al. Notch signalling controls pancreatic cell differentiation. Nature 1999;400:877¨C881.  V) y0 n0 a6 o8 c; B. T$ V9 ?7 C

Jensen J, Pedersen EE, Galante P et al. Control of endodermal endocrine development by Hes-1. Nat Genet 2000;24:36¨C44.

Fujikura J, Hosoda K, Iwakura H et al. Notch/Rbp-j signaling prevents premature endocrine and ductal cell differentiation in the pancreas. Cell Metab 2006;3:59¨C65.

Sumazaki R, Shiojiri N, Isoyama S et al. Conversion of biliary system to pancreatic tissue in Hes1-deficient mice. Nat Genet 2004;36:83¨C87.  a. _5 u6 S- X9 |# D% g6 I1 ?; q
$ T2 u, n, t8 z  X
Fre S, Huyghe M, Mourikis P et al. Notch signals control the fate of immature progenitor cells in the intestine. Nature 2005;435:964¨C968.

Powell BC, Passmore EA, Nesci A et al. The Notch signalling pathway in hair growth. Mech Dev 1998;78:189¨C192.2 j( r; c8 q' m( b
$ a, T/ G; \3 f
Pan Y, Lin MH, Tian X et al. Gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell 2004;7:731¨C743.
* K4 w7 B. d, r+ }5 o) S
Vauclair S, Nicolas M, Barrandon Y et al. Notch1 is essential for postnatal hair follicle development and homeostasis. Dev Biol 2005;284:184¨C193.

Lin MH, Leimeister C, Gessler M et al. Activation of the Notch pathway in the hair cortex leads to aberrant differentiation of the adjacent hair-shaft layers. Development 2000;127:2421¨C2432.$ {) c) m9 p4 W' f
' o. k3 z- Y- Q5 H& ~6 D' k( ~' N
Uyttendaele H, Panteleyev AA, de Berker D et al. Activation of Notch1 in the hair follicle leads to cell-fate switch and Mohawk alopecia. Differentiation 2004;72:396¨C409.+ k5 F& E- r, P. l1 W0 L; f. g$ }

Yamamoto N, Tanigaki K, Han H et al. Notch/RBP-J signaling regulates epidermis/hair fate determination of hair follicular stem cells. Curr Biol 2003;13:333¨C338.

Nicolas M, Wolfer A, Raj K et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 2003;33:416¨C421.) ~  ?" N: i* ~; D/ J- L

Radtke F, Raj K. The role of Notch in tumorigenesis: Oncogene or tumour suppressor? Nat Rev Cancer 2003;3:756¨C767.9 v1 n( T. l5 h2 b/ G* X+ n
8 }' h3 J# L! A1 S) X: ]
Zhang J, Niu C, Ye L et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 2003;425:836¨C841./ I/ h# P- _* x0 G) R# u/ K
, E3 S; o/ k, {& p
Calvi LM, Adams GB, Weibrecht KW et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 2003;425:841¨C846.
7 g1 J/ c% L( M
Arai F, Hirao A, Ohmura M et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 2004;118:149¨C161.
# F3 O0 e& a/ `. j% l1 _
Kiel MJ, Yilmaz OH, Iwashita T et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 2005;121:1109¨C1121.
" E5 u. C2 \' ?# m( C& p' R8 j
Duncan AW, Rattis FM, DiMascio LN et al. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nat Immunol 2005;6:314¨C322.
4 D0 Y1 J( S4 Z! D9 `
Mancini SJ, Mantei N, Dumortier A et al. Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation. Blood 2005;105:2340¨C2342.

von Kalle C, Glimm H, Schulz G et al. New developments in hematopoietic stem cell expansion. Curr Opin Hematol 1998;5:79¨C86.

Varnum-Finney B, Xu L, Brashem-Stein C et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nat Med 2000;6:1278¨C1281.; U" ^7 g* K3 P

Stier S, Cheng T, Dombkowski D et al. Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood 2002;99:2369¨C2378.

Kunisato A, Chiba S, Nakagami-Yamaguchi E et al. HES-1 preserves purified hematopoietic stem cells ex vivo and accumulates side population cells in vivo. Blood 2003;101:1777¨C1783.
) V% Y! q# L9 ]0 ~) Y
Varnum-Finney B, Purton LE, Yu M et al. The Notch ligand, Jagged-1, influences the development of primitive hematopoietic precursor cells. Blood 1998;91:4084¨C4091.
8 k! a1 E$ c2 E$ a
Jones P, May G, Healy L et al. Stromal expression of Jagged 1 promotes colony formation by fetal hematopoietic progenitor cells. Blood 1998;92:1505¨C1511.
6 s, ^6 d; O: p: T
Han W, Ye Q, Moore MA. A soluble form of human Delta-like-1 inhibits differentiation of hematopoietic progenitor cells. Blood 2000;95:1616¨C1625.
4 @* |8 h+ `4 D. g7 r8 p
Varnum-Finney B, Brashem-Stein C, Bernstein ID. Combined effects of Notch signaling and cytokines induce a multiple log increase in precursors with lymphoid and myeloid reconstituting ability. Blood 2003;101:1784¨C1789.- c7 o0 f* d3 L. _" x7 \6 g# ~5 g
0 V; t' N- u$ v7 x8 D, _
Vas V, Szilagyi L, Paloczi K et al. Soluble Jagged-1 is able to inhibit the function of its multivalent form to induce hematopoietic stem cell self-renewal in a surrogate in vitro assay. J Leukoc Biol 2004;75:714¨C720.: j$ B+ N2 k6 V

Walker L, Lynch M, Silverman S et al. The Notch/Jagged pathway inhibits proliferation of human hematopoietic progenitors in vitro. STEM CELLS 1999;17:162¨C171.
. Z% G! S% _1 P6 P6 |
Carlesso N, Aster JC, Sklar J et al. Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics. Blood 1999;93:838¨C848.. Z( A+ b; w& v  C2 E# U5 W
8 |3 _# L: H! a: @0 W
Karanu FN, Murdoch B, Gallacher L et al. The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells. J Exp Med 2000;192:1365¨C1372.2 C' K  V5 Y" E

Karanu FN, Murdoch B, Miyabayashi T et al. Human homologues of Delta-1 and Delta-4 function as mitogenic regulators of primitive human hematopoietic cells. Blood 2001;97:1960¨C1967.

Ohishi K, Varnum-Finney B, Bernstein ID. Delta-1 enhances marrow and thymus repopulating ability of human CD34( )CD38(¨C) cord blood cells. J Clin Invest 2002;110:1165¨C1174.
/ E2 V! K/ e' J+ v
Lauret E, Catelain C, Titeux M et al. Membrane-bound delta-4 notch ligand reduces the proliferative activity of primitive human hematopoietic CD34 CD38low cells while maintaining their LTC-IC potential. Leukemia 2004;18:788¨C797.
5 u; @6 _+ j+ R. D/ L( }
Dando JS, Tavian M, Catelain C et al. Notch/Delta4 interaction in human embryonic liver CD34  CD38¨C cells: Positive influence on BFU-E production and LTC-IC potential maintenance. STEM CELLS 2005;23:550¨C560./ C# \$ ^& u0 N6 ~

Delaney C, Varnum-Finney B, Aoyama K et al. Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells. Blood 2005;.

Suzuki T, Yokoyama Y, Kumano K et al. Highly efficient ex vivo expansion of human hematopoietic stem cells using Delta-Fc chimeric protein. STEM CELLS 10.1634/stemcells.2006-0258.' I$ ^/ m% B8 Z- Z5 I: d
4 `: S+ q3 q* C; Z
Radtke F, Wilson A, Stark G et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 1999;10:547¨C558.( D+ o. T5 P: ^* t" [
" D- Q' m' a) O+ ^
Pui JC, Allman D, Xu L et al. Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 1999;11:299¨C308.! ~- y, Y% [# M9 s

Wilson A, MacDonald HR, Radtke F. Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus. J Exp Med 2001;194:1003¨C1012.

Koch U, Lacombe TA, Holland D et al. Subversion of the T/B lineage decision in the thymus by lunatic fringe-mediated inhibition of Notch-1. Immunity 2001;15:225¨C236.# r) s- P2 \* B' S
5 d; o  _* V5 `/ R
Hadland BK, Manley NR, Su D et al. Gamma-secretase inhibitors repress thymocyte development. Proc Natl Acad Sci U S A 2001;98:7487¨C7491.  W8 r# `# D* h, D) b5 }7 a9 H

Wolfer A, Wilson A, Nemir M, MacDonald HR, Radtke F. Inactivation of Notch1 impairs VDJbeta rearrangement and allows pre-TCR-independent survival of early alpha beta lineage thymocytes. Immunity 2002;16:869¨C879.1 c  S7 V7 z% s. H

Lehar SM, Dooley J, Farr AG et al. Notch ligands Delta 1 and Jagged1 transmit distinct signals to T-cell precursors. Blood 2005;105:1440¨C1447.( R: f' b8 u4 P' [
1 o, Q) |2 h  e, K! E% b$ \, V
Ciofani M, Zuniga-Pflucker JC. Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism. Nat Immunol 2005;6:881¨C888.

Tanigaki K, Han H, Yamamoto N et al. Notch-RBP-J signaling is involved in cell fate determination of marginal zone B cells. Nat Immunol 2002;3:443¨C450.! K2 X5 R" Q1 a" z$ m
4 d% k/ Y* ~7 F3 n  M5 j1 H
Kuroda K, Han H, Tani S et al. Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway. Immunity 2003;18:301¨C312.
# t8 C& Z3 V* k# h$ \+ k5 ^  O
Saito T, Chiba S, Ichikawa M et al. Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity 2003;18:675¨C685.
$ X9 n2 ~- H* K' W2 s
Hozumi K, Negishi N, Suzuki D et al. Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo. Nat Immunol 2004;5:638¨C644.5 C" S' V- E- Q% O& b

Sambandam A, Maillard I, Zediak VP et al. Notch signaling controls the generation and differentiation of early T lineage progenitors. Nat Immunol 2005;6:663¨C670.  F- P  {+ i9 c$ `
. ]3 m4 i* k& S& d8 |1 w
Schmitt TM, Zuniga-Pflucker JC. Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity 2002;17:749¨C756.
: a3 z0 F+ j* T/ g9 x* c- L
Rothenberg EV. T-lineage specification and commitment: A gene regulation perspective. Semin Immunol 2002;14:431¨C440.

Zuniga-Pflucker JC. T-cell development made simple. Nat Rev Immunol 2004;4:67¨C72.# K1 c+ g; @( G* |

Leedham SJ, Brittan M, McDonald SA et al. Intestinal stem cells. J Cell Mol Med 2005;9:11¨C24.3 w5 R8 q  Z; C
/ b( J5 q3 b, l7 I. n* z% f
Schonhoff SE, Giel-Moloney M, Leiter AB. Minireview: Development and differentiation of gut endocrine cells. Endocrinology 2004;145:2639¨C2644.
4 X; s6 t3 s3 }1 K
Schroder N, Gossler A. Expression of Notch pathway components in fetal and adult mouse small intestine. Gene Expr Patterns 2002;2:247¨C250.
0 ~( B$ y6 s, d; U- d5 Q% F# N
Sander GR, Powell BC. Expression of notch receptors and ligands in the adult gut. J Histochem Cytochem 2004;52:509¨C516.0 y1 D, q, m( q8 ?& M2 l% n' X/ i

Searfoss GH, Jordan WH, Calligaro DO et al. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem 2003;278:46107¨C46116.

Wong GT, Manfra D, Poulet FM et al. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 2004;279:12876¨C12882.9 ~, j( _- T9 W6 \- f

Milano J, McKay J, Dagenais C et al. Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci 2004;82:341¨C358.
5 X3 T2 f1 I- q: b6 Z) \5 q
van Es JH, van Gijn ME, Riccio O et al. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 2005;435:959¨C963.$ W0 H4 @- L  }7 ~/ f

Collins CA, Olsen I, Zammit PS et al. Stem cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell niche. Cell 2005;122:289¨C301.

Conboy IM, Conboy MJ, Wagers AJ et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 2005;433:760¨C764.5 A3 [$ r$ N) R7 j6 X/ }7 t

Conboy IM, Rando TA. The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis. Dev Cell 2002;3:397¨C409.

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