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-1Δ/Δ 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.
ACKNOWLEDGMENTS
We thank Annie De Smet for excellent technical assistance with ES cell handling and cytometry analysis, Rachid Zoubairi for mouse breeding and handling, Patricia Wattier for preparation of histological sections, Corinne Garcia for performing cell sorting, and the Service d’Experimentation animale et de transgénèse for the generation of mutant mice. We thank Simon Fillatreau for his advice on immunizations and ELISA tests, Barbara Bertocci for advice on cytometry analysis, and Michel Cogné for help and advice on the induction of isotype switching in vitro. We thank Warren Pear for providing the E2A reporter and Meinrad Busslinger for providing CD19-CRE mice. We also thank Auriel Dahan for his continuous support throughout this work.
This work was supported by grants from the Ministère de la Recherche (ACI Biologie du Développement et Physiologie Intégrative) and the Fondation Princesse Grace. S.S. was supported by grants from the Ministère de l'Education Nationale de la Recherche et de la Technologie and the Association pour la Recherche contre le Cancer.