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Normal immune system development in mice lacking the Deltex-1 RING finger domain.

ABSTRACT: The Notch signaling pathway controls several cell fate decisions during lymphocyte development, from T-cell lineage commitment to the peripheral differentiation of B and T lymphocytes. Deltex-1 is a RING finger ubiquitin ligase which is conserved from Drosophila to humans and has been proposed to be a regulator of Notch signaling. Its pattern of lymphoid expression as well as gain-of-function experiments suggest that Deltex-1 regulates both B-cell lineage and splenic marginal-zone B-cell commitment. Deltex-1 was also found to be highly expressed in germinal-center B cells. To investigate the physiological function of Deltex-1, we generated a mouse strain lacking the Deltex-1 RING finger domain, which is essential for its ubiquitin ligase activity. Deltex-1(Delta/Delta) mice were viable and fertile. A detailed histological analysis did not reveal any defects in major organs. T- and B-cell development was normal, as were humoral responses against T-dependent and T-independent antigens. These data indicate that the Deltex-1 ubiquitin ligase activity is dispensable for mouse development and immune function. Possible compensatory mechanisms, in particular those from a fourth Deltex gene identified during the course of this study, are also discussed.

SUBMITTER: Storck S

PROVIDER: S-EPMC548011 | biostudies-literature | 2005 Feb

REPOSITORIES: biostudies-literature

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Normal immune system development in mice lacking the Deltex-1 RING finger domain.

Storck Sébastien S Delbos Frédéric F Stadler Nicolas N Thirion-Delalande Catherine C Bernex Florence F Verthuy Christophe C Ferrier Pierre P Weill Jean-Claude JC Reynaud Claude-Agnès CA

Molecular and cellular biology 20050201 4

The Notch signaling pathway controls several cell fate decisions during lymphocyte development, from T-cell lineage commitment to the peripheral differentiation of B and T lymphocytes. Deltex-1 is a RING finger ubiquitin ligase which is conserved from Drosophila to humans and has been proposed to be a regulator of Notch signaling. Its pattern of lymphoid expression as well as gain-of-function experiments suggest that Deltex-1 regulates both B-cell lineage and splenic marginal-zone B-cell commitm ...[more]

PMID: 15684394

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Project description:BackgroundCampylobacter jejuni infections are of rising importance worldwide. Given that innate immune receptors including nucleotide-oligomerization-domain-2 (Nod2) are essentially involved in combating enteropathogenic infections, we here surveyed the impact of Nod2 in murine campylobacteriosis.Methods and resultsIn order to overcome physiological colonization resistance preventing from C. jejuni infection, we generated secondary abiotic Nod2-/- and wildtype (WT) mice by broad-spectrum antibiotic treatment. Mice were then perorally infected with C. jejuni strain 81-176 on 2 consecutive days and could be stably colonized by the pathogen at high loads. Notably, Nod2 deficiency did not affect gastrointestinal colonization properties of C. jejuni. Despite high intestinal pathogenic burdens mice were virtually uncompromised and exhibited fecal blood in single cases only. At day 7 postinfection (p.i.) similar increases in numbers of colonic epithelial apoptotic cells could be observed in mice of either genotype, whereas C. jejuni infected Nod2-/- mice displayed more distinct regenerative properties in the colon than WT controls. C. jejuni infection was accompanied by increases in distinct immune cell populations such as T lymphocytes and regulatory T cells in mice of either genotype. Increases in T lymphocytes, however, were less pronounced in large intestines of Nod2-/- mice at day 7 p.i. when compared to WT mice, whereas colonic numbers of B lymphocytes were elevated in WT controls only upon C. jejuni infection. At day 7 p.i., colonic pro-inflammatory mediators including nitric oxide, TNF, IFN-? and IL-22 increased more distinctly in Nod2-/- as compared to WT mice, whereas C. jejuni induced IL-23p19 and IL-18 levels were lower in the large intestines of the former. Converse to the colon, however, ileal concentrations of nitric oxide, TNF, IFN-?, IL-6 and IL-10 were lower in Nod2-/- as compared to WT mice at day 7 p.i. Even though MUC2 was down-regulated in C. jejuni infected Nod2-/- mice, this did not result in increased pathogenic translocation from the intestinal tract to extra-intestinal compartments.ConclusionIn secondary abiotic mice, Nod2 signaling is involved in the orchestrated host immune responses upon C. jejuni infection, but does not control pathogen loads in the gastrointestinal tract.

Project description:Cardiac myosin binding protein C (cMyBP-C) is an essential regulator of cross bridge cycling. Through mechanisms that are incompletely understood the N-terminal domains (NTDs) of cMyBP-C can activate contraction even in the absence of calcium and can also inhibit cross bridge kinetics in the presence of calcium. In vitro studies indicated that the proline-alanine rich (p/a) region and C1 domain are involved in these processes, although effects were greater using human proteins compared to murine proteins (Shaffer et al. J Biomed Biotechnol 2010, 2010: 789798). We hypothesized that the p/a and C1 region are critical for the timing of contraction. In this study we tested this hypothesis using a mouse model lacking the p/a and C1 region (p/a-C1(-/-) mice) to investigate the in vivo relevance of these regions on cardiac performance. Surprisingly, hearts of adult p/a-C1(-/-) mice functioned normally both on a cellular and whole organ level. Force measurements in permeabilized cardiomyocytes from adult p/a-C1(-/-) mice and wild type (Wt) littermate controls demonstrated similar rates of force redevelopment both at submaximal and maximal activation. Maximal and passive force and calcium sensitivity of force were comparable between groups as well. Echocardiograms showed normal isovolumetric contraction times, fractional shortening and ejection fraction, indicating proper systolic function in p/a-C1(-/-) mouse hearts. p/a-C1(-/-) mice showed a slight but significant reduction in isovolumetric relaxation time compared to Wt littermates, yet this difference disappeared in older mice (7-8months of age). Moreover, stroke volume was preserved in p/a-C1(-/-) mice, corroborating sufficient time for normal filling of the heart. Overall, the hearts of p/a-C1(-/-) mice showed no signs of dysfunction even after chronic stress with an adrenergic agonist. Together, these results indicate that the p/a region and the C1 domain of cMyBP-C are not critical for normal cardiac contraction in mice and that these domains have little if any impact on cross bridge kinetics in mice. These results thus contrast with in vitro studies utilizing proteins encoding the human p/a region and C1 domain. More detailed insight in how individual domains of cMyBP-C function and interact, across species and over the wide spectrum of conditions in which the heart has to function, will be essential to a better understanding of how cMyBP-C tunes cardiac contraction.

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Normal immune system development in mice lacking the Deltex-1 RING finger domain.

Publications

Normal immune system development in mice lacking the Deltex-1 RING finger domain.

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