Ron-mediated cytoplasmic signaling is dispensable for viability but is required to limit inflammatory responses
Susan E. Waltz, … , Klaus H. Kaestner, Sandra J.F. Degen
Susan E. Waltz, … , Klaus H. Kaestner, Sandra J.F. Degen
Published August 15, 2001
Citation Information: J Clin Invest. 2001;108(4):567-576. https://doi.org/10.1172/JCI11881.
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Article

Ron-mediated cytoplasmic signaling is dispensable for viability but is required to limit inflammatory responses

Abstract

Ron receptor activation induces numerous cellular responses in vitro, including proliferation, dissociation, and migration. Ron is thought to be involved in blood cell development in vivo, as well as in many aspects of the immune response including macrophage activation, antigen presentation, and nitric oxide regulation. In previous studies to determine the function of Ron in vivo, mice were generated with a targeted deletion of the extracellular and transmembrane regions of this gene. Mice homologous for this deletion appear to die early during embryonic development. To ascertain the in vivo function of Ron in more detail, we have generated mice with a germline ablation of the tyrosine kinase domain. Strikingly, our studies indicate that this domain of Ron, and therefore Ron cytoplasmic signaling, is not essential for embryonic development. While mice deficient in this domain are overtly normal, mice lacking Ron signaling have an altered ability to regulate nitric oxide levels and, in addition, have enhanced tissue damage following acute and cell-mediated inflammatory responses.

Authors

Susan E. Waltz, Laura Eaton, Kenya Toney-Earley, Karla A. Hess, Belinda E. Peace, Jeffrey R. Ihlendorf, Ming-Hai Wang, Klaus H. Kaestner, Sandra J.F. Degen

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Figure 1

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Shown are the Ron genomic locus (A1), the targeting vector (A2), the res...
Shown are the Ron genomic locus (A1), the targeting vector (A2), the resulting locus obtained after homologous recombination (A3), and the resulting products obtained after Cre recombinase–mediated excision (A4, A5, A6). LoxP recombinase recognition sites are indicated by arrows. Homologous arms are indicated by text and by dotted lines. Exons are indicated by black boxes. Probes for Southern blot analyses are indicated. Restriction enzyme notations are as follows, with underlining representing sites specific for the targeted locus: B, BamH1; RI, EcoR1. (b) Southern blot analysis of a positively selected ES clone (12) following electroporation of the targeting vector. (c) Transient transfection of targeted ES cell clone O12 with Cre recombinase will result in three types of Cre-mediated excision (A4, A5, A6). Transient transfected ES cell lysates were digested with EcoR and were probed with probe B. Lanes 1 and 2 have DNA from ES cell clones that have undergone the A4 recombination event, while loss of the TK domain in lanes 3–6 suggests ES cells clones were obtained from the A5 recombination event. (d) Southern blot analysis of BamHI-digested DNA isolated from mice of Ron TK+/– crosses containing the A5 recombination event, probed with probe A.