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Conditional Deletion (conditional + deletion)
Selected AbstractsFoxo1 regulates marginal zone B-cell developmentEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2010Jing Chen Abstract A fundamental component of signaling initiated by the BCR and CD19 is the activation of phosphoinositide 3-kinase. Downstream of phosphoinositide 3-kinase, the protein kinase AKT phosphorylates several substrates, including members of the forkhead box subgroup O (Foxo) transcription factor family. Among the Foxo proteins, Foxo1 has unique functions in bone marrow B-cell development and peripheral B-cell function. Here, we report a previously unrecognized role for Foxo1 in controlling the ratio of mature B-cell subsets in the spleen. Conditional deletion of Foxo1 in B cells resulted in an increased percentage of marginal zone B cells and a decrease in follicular (FO) B cells. In addition, Foxo1 deficiency corrected the absence of marginal zone B cells that occurs in CD19-deficient mice. These findings show that Foxo1 regulates the balance of mature B-cell subsets and is required for the marginal zone B-cell deficiency phenotype of mice lacking CD19. [source] The canonical Wnt signaling pathway plays an important role in lymphopoiesis and hematopoiesisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2008Frank Abstract The evolutionarily conserved canonical Wnt-,-catenin-T cell factor (TCF)/lymphocyte enhancer binding factor (LEF) signaling pathway regulates key checkpoints in the development of various tissues. Therefore, it is not surprising that a large body of gain-of-function and loss-of-function studies implicate Wnt-,-catenin signaling in lymphopoiesis and hematopoiesis. In contrast, recent papers have reported that Mx-Cre-mediated conditional deletion of ,-catenin and/or its homolog ,-catenin (plakoglobin) did not impair hematopoiesis or lymphopoiesis. However, these studies also report that TCF reporter activity remains active in ,-catenin- and ,-catenin-deficient hematopoietic stem cells and all cells derived from these precursors, indicating that the canonical Wnt signaling pathway was not abrogated. Therefore, these studies in fact show that the canonical Wnt signaling pathway is important in hematopoiesis and lymphopoiesis, even though the molecular basis for the induction of the reporter activity is currently unknown. In this perspective, we provide a broad background to the field with a discussion of the available data and create a framework within which the available and future studies may be evaluated. [source] The essential haematopoietic transcription factor Scl is also critical for neuronal developmentEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2006Cara K. Bradley Abstract The basic helix-loop-helix (bHLH) transcription factor Scl displays tissue-restricted expression and is critical for the establishment of the haematopoietic system; loss of Scl results in embryonic death due to absolute anaemia. Scl is also expressed in neurons of the mouse diencephalon, mesencephalon and metencephalon; however, its requirement in those sites remains to be determined. Here we report conditional deletion of Scl in neuronal precursor cells using the Cre/LoxP system. Neuronal-Scl deleted mice died prematurely, were growth retarded and exhibited an altered motor phenotype characterized by hyperactivity and circling. Moreover, ablation of Scl in the nervous system affected brain morphology with abnormal neuronal development in brain regions known to express Scl under normal circumstances; there was an almost complete absence of Scl-null neurons in the hindbrain and partial loss of Scl-null neurons in the thalamus and midbrain from early neurogenesis onwards. Our results demonstrate a crucial role for Scl in the development of Scl-expressing neurons, including ,-aminobutyric acid (GABA)ergic interneurons. Our study represents one of the first demonstrations of functional overlap of a single bHLH protein that regulates neural and haematopoietic cell development. This finding underlines Scl's critical function in cell fate determination of mesodermal as well as neuroectodermal tissues. [source] Generation of a conditional allele of the mouse prostaglandin EP4 receptorGENESIS: THE JOURNAL OF GENETICS AND DEVELOPMENT, Issue 1 2004André Schneider Abstract Genetic disruption of the mouse EP4 receptor results in perinatal lethality associated with persistent patent ductus areteriosus (PDA). To circumvent this, an EP4 allele amenable to conditional deletion using the Cre/loxP system was generated. The targeting construct was comprised of a floxed exon2 in tandem with the neomycin-resistance gene in intron 2, flanked by third 3, LoxP site. Mice homozygous for the targeted allele (EP4lox+neo/lox+neo), or following its Cre -mediated deletion (EP4del/del), also die within hours of birth with PDA. In contrast, mice homozygous for a partially recombined allele, retaining exon2 but lacking neo (EP4flox/flox), are viable and show no overt phenotype. Postnatal deletion of the floxed EP4 gene is efficiently achieved in the liver and kidney in a transgenic mouse expressing the inducible Mx1Cre recombinase. The EP mouse should provide a useful reagent with which to examine the physiologic roles of the EP4 receptor. genesis 40:7,14, 2004. © 2004 Wiley-Liss, Inc. [source] Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell,specific signal transducer and activator of transcription 3 gene knockout mice,HEPATOLOGY, Issue 5 2010Norio Horiguchi Liver injury is associated with inflammation, which is generally believed to accelerate the progression of liver diseases; however, clinical data show that inflammation does not always correlate with hepatocelluar damage in some patients. Investigating the cellular mechanisms underlying these events using an experimental animal model, we show that inflammation may attenuate liver necrosis induced by carbon tetrachloride (CCl4) in myeloid-specific signal transducer and activator of transcription 3 (STAT3) knockout mice. As an important anti-inflammatory signal, conditional deletion of STAT3 in myeloid cells results in markedly enhanced liver inflammation after CCl4 injection. However, these effects are also accompanied by reduced liver necrosis, correlating with elevated serum interleukin-6 (IL-6) and hepatic STAT3 activation. An additional deletion of STAT3 in hepatocytes in myeloid-specific STAT3 knockout mice restored hepatic necrosis but decreased liver inflammation. Conclusion: Inflammation-mediated STAT3 activation attenuates hepatocellular injury induced by CCl4 in myeloid-specific STAT3 knockout mice, suggesting that inflammation associated with a predominance of hepatoprotective cytokines that activate hepatic STAT3 may reduce rather than accelerate hepatocellular damage in patients with chronic liver diseases. Hepatology 2010 [source] Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity,HEPATOLOGY, Issue 4 2010Hua Wang Liver regeneration triggered by two-thirds partial hepatectomy is accompanied by elevated hepatic levels of endotoxin, which contributes to the regenerative process, but liver inflammation and apoptosis remain paradoxically limited. Here, we show that signal transducer and activator of transcription 3 (STAT3), an important anti-inflammatory signal, is activated in myeloid cells after partial hepatectomy and its conditional deletion results in an enhanced inflammatory response. Surprisingly, this is accompanied by an improved rather than impaired regenerative response with increased hepatic STAT3 activation, which may contribute to the enhanced liver regeneration. Indeed, conditional deletion of STAT3 in both hepatocytes and myeloid cells results in elevated activation of STAT1 and apoptosis of hepatocytes, and a dramatic reduction in survival after partial hepatectomy, whereas additional global deletion of STAT1 protects against these effects. Conclusion: An interplay of myeloid and hepatic STAT3 signaling is essential to prevent liver failure during liver regeneration through tempering a strong innate inflammatory response mediated by STAT1 signaling. (HEPATOLOGY 2010.) [source] A new bone to pick: osteoblasts and the haematopoietic stem-cell nicheBIOESSAYS, Issue 6 2004Jiang Zhu Two recent publications highlight the role of bone-forming cells, the osteoblasts, in controlling the development of neighboring haematopoietic stem cells (HSCs).1,2 Using two distinct transgenic mouse models, one using the conditional deletion of the Bone Morphogenetic Protein Receptor 1A (BMPR1A) gene, the other using over-expression of an active PTH/PTHrP receptor (PPR) mutant within osteoblasts, the authors show parallel, concordant increases in the generation of trabecular osteoblasts and the number of HSCs. In situ staining showed that rarely cycling HSCs sporadically attach to endosteal osteoblasts, while in vitro assays indicated that ligation of Jag1 on osteoblasts by Notch1 on HSCs promotes HSC proliferation. These two independent works have revived and revitalized the notion that osteoblasts are a major, defining component of the HSC niche within the bone marrow (BM). This minireview discusses these results in the context of other recent studies of mesenchymal cells within the BM microenvironment, presents one potential unified model of the functional anatomy of the BM HSC niche, and highlights new questions raised by these and other studies of osteoblasts and HSCs. BioEssays 26:595,599, 2004. © 2004 Wiley Periodicals, Inc. [source] | |||||||||||||