Genetic Deletion of Murine SPRY Domain-Containing SOCS Box Protein 2 (SSB-2) Results in Very Mild Thrombocytopenia

Abstract

The SSB family is comprised of four highly homologous proteins containing a C-terminal SOCS box motif and a central SPRY domain. No function has yet been ascribed to any member of this family in mammalian species despite a clear role for other SOCS proteins in negative regulation of cytokine signaling. To investigate its physiological role, the murine Ssb-2 gene was deleted by homologous recombination. SSB-2-deficient mice were shown to have a reduced rate of platelet production, resulting in very mild thrombocytopenia (25% decrease in circulating platelets). Tissue histology and other hematological parameters were normal, as was the majority of serum biochemistry, with the exception that blood urea nitrogen (BUN) levels were decreased in mice lacking SSB-2. Quantitative analysis of SSB mRNA levels indicated that SSB-1, -2, and -3 were ubiquitously expressed; however, SSB-4 was only expressed at very low levels. SSB-2 expression was observed in the kidney and in megakaryocytes, a finding consistent with the phenotype of mice lacking this gene. Deletion of SSB-2 thus perturbs the steady-state level of two tightly controlled homeostatic parameters and identifies a critical role for SSB-2 in regulating platelet production and BUN levels.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/.

ACKNOWLEDGMENTS

This study was supported by the National Health and Medical Research Council (NHMRC) of Australia (program grant 257500), the Australian Federal Government Cooperative Research Centres Program, and AMRAD Operations Pty., Ltd., Melbourne, Australia. S.E.N. was supported by an NHMRC Biomedical Career Development award.

We thank F. Kupresanin, S. Mifsud, L. DiRago, S. Raker, C. Hyland, W. Carter, and J. Corbin for expert technical assistance and M. Carpinelli, B. Croker, and D. Krebs for helpful advice. We also thank S. Ellis for electron microscopy and T. Kemp, K. Vella, and G. Siciliano for animal experimentation and husbandry.