Inducible Gene Targeting in Mice

Kühn, Ralf; Schwenk, Frieder; Aguet, Michel; Rajewsky, Klaus

doi:10.1126/science.7660125

Cited by 1,729 publications

(1,498 citation statements)

References 19 publications

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“…In contrast to CD8 + lymphocytes in primary and secondary lymphoid tissues, a significant number of donor IEL maintained b 1 integrin expression (Fig. 2B, C), consistent with reports from other investigators demonstrating less efficient induction of gene deletion in the intestinal compartment as compared with primary and secondary lymphoid organs [19,20]. Finally, the degree of b 1 deletion was slightly greater for type a than type b IEL subsets (Fig.…”

Section: Mouse Small Intestinal Iel Express Functional B 1 Integrinssupporting

confidence: 89%

β1 integrins are not required for the maintenance of lymphocytes within intestinal epithelia

et al. 2005

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b 1 integrins are thought to play a central role in maintaining lymphocytes within mucosal epithelia via their interactions with extracellular matrix proteins and subepithelial cellular components within and underlying the basement membrane. In the current study type a (CD8abTCRab) and type b (CD8aaTCRcd and CD8aaTCRab) intraepithelial lymphocyte (IEL) subsets within the mouse small intestine were found to express functional b 1 integrin and the b 1 integrin a chain partners a 1 , a 2 , and a 4 . Using inducible b 1 integrin-knockout bone marrow-chimeric mice we demonstrate that IEL expression of a 1 and a 2 but not a 4 is dependent on expression of the b 1 chain. Importantly, deletion of the b 1 chain in IEL did not alter the number or composition of lymphocytes within the intestinal epithelium. Thus, while IEL express functional b 1 integrins, these are not required to maintain lymphocytes within intestinal epithelia. This result is discussed in the light of conventional views of intestinal lymphocyte homing and localization.

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Section: Mouse Small Intestinal Iel Express Functional B 1 Integrinssupporting

confidence: 89%

β1 integrins are not required for the maintenance of lymphocytes within intestinal epithelia

et al. 2005

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“…We then mated EHKI Neo þ mice with MxCre transgenic mice that express Cre under the control of the interferon-responsive Mx promoter (Kuhn et al, 1995). EHKI Neo þ /MxCre compound mice were injected with polyinosinic/polycytidylic acid (pIpC), which is a strong and transient inducer of interferon, to delete the floxed Neo gene from the knocked-in allele and to create Neodeleted (EHKI DNeo ) mice (Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia

et al. 2010

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E2A-hepatic leukemia factor (HLF) is a chimeric protein found in B-lineage acute lymphoblastic leukemia (ALL) with t(17;19). To analyze the leukemogenic process and to create model mice for t(17;19)-positive leukemia, we generated inducible knock-in (iKI) mice for E2A-HLF. Despite the induced expression of E2A-HLF in the hematopoietic tissues, no disease was developed during the long observation period, indicating that additional gene alterations are required to develop leukemia. To elucidate this process, E2A-HLF iKI and control littermates were subjected to retroviral insertional mutagenesis. Virus infection induced acute leukemias in E2A-HLF iKI mice with higher morbidity and mortality than in control mice. Inverse PCR detected three common integration sites specific for E2A-HLF iKI leukemic mice, which induced overexpression of zinc-finger transcription factors: growth factor independent 1 (Gfi1), zinc-finger protein subfamily 1A1 isoform a (Zfp1a1, also known as Ikaros) and zinc-finger protein 521 (Zfp521). Interestingly, tumors with Zfp521 integration exclusively showed B-lineage ALL, which corresponds to the phenotype of human t(17;19)-positive leukemia. In addition, ZNF521 (human counterpart of Zfp521) was found to be overexpressed in human leukemic cell lines harboring t(17;19). Moreover, both iKI for E2A-HLF and transgenic for Zfp521 mice frequently developed B-lineage ALL. These results indicate that a set of transcription factors promote leukemic transformation of E2A-HLF-expressing hematopoietic progenitors and suggest that aberrant expression of Zfp521/ZNF521 may be clinically relevant to t(17;19)-positive B-lineage ALL.

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“…Animal experiments were approved by the Animal Experimentation Committee of Tokai University. Jagged1‐floxed knockin mice ( Jagged1 lox/lox )12 were crossed with Mx‐Cre transgenic mice13 to generate polyinosinic‐polycytidylic acid [poly(I):poly(C)]‐inducible Jagged1 cKO mice. Notch2 ‐floxed knockin mice ( Notch2 lox/lox )14 were mated with Albumin‐Cre transgenic mice15 [C57BL/6TgN(AlbCre)21Mgn strain from Jackson Laboratory, Bar Harbor, ME] to achieve hepatocyte‐specific Notch2 gene deletion.…”

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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Inducible Gene Targeting in Mice

Cited by 1,729 publications

References 19 publications

β1 integrins are not required for the maintenance of lymphocytes within intestinal epithelia

β1 integrins are not required for the maintenance of lymphocytes within intestinal epithelia

Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia

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

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