Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo

Hozumi, Katsuto; Negishi, Naoko; Suzuki, Daisuke; Abe, Natsumi; Sotomaru, Yusuke; Tamaoki, Norikazu; Mailhos, Carolina; Ish‐Horowicz, David; Habu, Sonoko; Owen, Michael John

doi:10.1038/ni1075

Cited by 301 publications

(334 citation statements)

References 39 publications

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“…Moreover, when BM progenitors are co-cultured on stromal cells overexpressing DL1, B cell development is blocked ( 15 ). Surprisingly, in contrast with these promising data obtained in vitro, conditional inactivation of DL1 in thymocytes and/or thymic epithelial cells (TECs) does not inhibit T cell development ( 16 ). This discrepancy may be caused by the in vivo presence of DL4, which shares a high degree of homology mRNA expression of the DL1 -driven lacZ gene is confi ned to blood vessels within the thymus, whereas DL4 drives expression preferentially within the cortical epithelium.…”

Section: Resultsmentioning

confidence: 48%

Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment

Koch¹,

Fiorini²,

Benedito³

et al. 2008

J Cell Biol

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The thymus is continuously seeded by progenitors derived from hematopoietic stem cells, which reside in the BM. These progenitors migrate via the blood stream into the thymus, where they adopt a T cell fate, proliferate, and diff erentiate into mature functional T cells. This differentiation process is characterized by multiple developmental stages. The earliest thymic progenitors lack surface expression of CD4 and CD8 and are therefore referred to as doublenegative (DN) thymocytes. They subsequently up-regulate both CD4 and CD8 coreceptors (double positive [DP]) before undergoing positive and negative selection, and maturing to CD4 and CD8 single-positive (SP) thymocytes that emigrate to the periphery. Immature DN thymocytes can be subdivided into four subpopulations according to the surface expression of CD117, CD44, and CD25. The most immature thymocyte progenitors (DN1) express CD117 and CD44 and are negative for CD25, followed by the DN2 population, which upregulates CD25, and the DN3 cells, which downregulate CD117 and CD44 before generating DN4 thymocytes lacking expression of all three markers ( 1, 2 ).Over the last decade, many reports highlighted the importance of the evolutionarily conserved Notch cascade for the lymphoid system ( 3 ). Mammals possess 4 Notch receptors (N1 -4), which are activated by two classes of Thymic T cell lineage commitment is dependent on Notch1 (N1) receptor -mediated signaling. Although the physiological ligands that interact with N1 expressed on thymic precursors are currently unknown, in vitro culture systems point to Delta-like 1 (DL1) and DL4 as prime candidates. Using DL1 -and DL4-lacZ reporter knock-in mice and novel monoclonal antibodies to DL1 and DL4, we show that DL4 is expressed on thymic epithelial cells (TECs), whereas DL1 is not detected. The function of DL4 was further explored in vivo by generating mice in which DL4 could be specifi cally inactivated in TECs or in hematopoietic progenitors. Although loss of DL4 in hematopoietic progenitors did not perturb thymus development, inactivation of DL4 in TECs led to a complete block in T cell development coupled with the ectopic appearance of immature B cells in the thymus. These immature B cells were phenotypically indistinguishable from those developing in the thymus of conditional N1 mutant mice. Collectively, our results demonstrate that DL4 is the essential and nonredundant N1 ligand responsible for T cell lineage commitment. Moreover, they strongly suggest that N1-expressing thymic progenitors interact with DL4-expressing TECs to suppress B lineage potential and to induce the fi rst steps of intrathymic T cell development.

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Section: Resultsmentioning

confidence: 48%

Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment

Koch¹,

Fiorini²,

Benedito³

et al. 2008

J Cell Biol

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“…Their genotypes were determined by polymerase chain reaction (PCR) using the primer sets listed in Supporting Table S1. At 8 weeks of age, Jagged1 cKO mice and control Mx‐Cre ‐negative Jagged1 lox/lox littermates were given a total of four injections of 250 μg of poly(I):poly(C) (Sigma‐Aldrich, St. Louis, MO) every 3 days 16. Approximately 8 weeks after the poly(I):poly(C) injections, the mice started to receive subcutaneous injections of 1 mL/kg body weight of CCl 4 (Wako Pure Chemical Industries, Ltd., Tokyo, Japan) mixed in olive oil every 3 days for a total of 28‐30 times 17.…”

Section: Methodsmentioning

confidence: 99%

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

Nakano

Nakao

Sumiyoshi

et al. 2017

Hepatology Communications

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The liver is well known to possess high regenerative capacity in response to partial resection or tissue injury. However, liver regeneration is often impaired in the case of advanced liver fibrosis/cirrhosis when mature hepatocytes can hardly self‐proliferate. Hepatic progenitor cells have been implicated as a source of hepatocytes in regeneration of the fibrotic liver. Although alpha‐fetoprotein (AFP) is known as a clinical marker of progenitor cell induction in injured/fibrotic adult liver, the origin and features of such AFP‐producing cells are not fully understood. Here, we demonstrate a unique and distinct AFP‐expressing cell population that is induced by the Jagged1/Notch2 signal in murine fibrotic liver. Following repeated carbon tetrachloride injections, a significant number of AFP‐positive cells with high proliferative ability were observed along the fibrous septa depending on the extent of liver fibrosis. These AFP‐positive cells exhibited features of immature hepatocytes that were stained positively for hepatocyte‐lineage markers, such as albumin and hepatocyte nuclear factor 4 alpha, and a stem/progenitor cell marker Sox9. A combination of immunohistological examination of fibrotic liver tissues and coculture experiments with primary hepatocytes and hepatic stellate cells indicated that increased Jagged1 expression in activated hepatic stellate cells stimulated Notch2 signaling and up‐regulated AFP expression in adjacent hepatocytes. The mobilization and proliferation of AFP‐positive cells in fibrotic liver were further enhanced after partial hepatectomy, which was significantly suppressed in Jagged1‐conditional knockout mice. Finally, forced expression of the intracellular domain of Notch2 in normal liver induced a small number of AFP‐expressing hepatocytes in vivo. Conclusion: Insight is provided into a novel pathophysiological role of Jagged1/Notch2 signaling in the induction of AFP‐positive cells in fibrotic liver through the interaction between hepatocytes and activated hepatic stellate cells. (Hepatology Communications 2017;1:215‐229)

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“…Loss of the Notch1 receptor perturbs T-cell development, yet the B-cell compartment appears unaffected (Radtke et al, 1999). Conversely, the targeted inactivation of the Notch2 receptor or Dll1 ligand results in a loss of marginal zone B cells (MZB cells), but T-cell development appears normal (Saito et al, 2003;Hozumi et al, 2004). Importantly, these effects are consistent with phenotypes caused by the inactivation of canonical Notch signaling in these compartments, because loss of the transcription factor CSL blocks both T-cell development and MZB cell generation Tanigaki et al, 2002).…”

Section: Identification Of Maml Proteins and Investigations Into Theimentioning

confidence: 99%

Mastermind-like transcriptional co-activators: emerging roles in regulating cross talk among multiple signaling pathways

2008

Oncogene

133

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Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo

Cited by 301 publications

References 39 publications

Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment

Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

Mastermind-like transcriptional co-activators: emerging roles in regulating cross talk among multiple signaling pathways

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