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Regulation of Lymphocyte Development by Cell-Type-Specific Interpretation of Notch Signals

Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, Oklahoma 73104,¹ Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455²

Received 14 May 2007/ Returned for modification 18 June 2007/ Accepted 28 December 2007

Notch signaling pathways exert diverse biological effects depending on the cellular context where Notch receptors are activated. How Notch signaling is integrated with environmental cues is a central issue. Here, we show that Notch activation accelerates ubiquitin-mediated and mitogen-activated protein kinase (MAPK)-dependent degradation of E2A transcription factors and Janus kinases, molecules essential for both B- and T-lymphocyte development. However, these events occur in B lymphocytes, but not T lymphocytes, due to their different levels of MAPK, thus providing one mechanism whereby Notch inhibits B-cell development without impairing T-cell differentiation. Lymphoid progenitors expressing a Notch-resistant E2A mutant differentiated into B-lineage cells on stromal cells expressing Notch ligands and in the thymus of transplant recipients. Bone marrow transplant assays and examination of steady-state B lymphopoiesis also revealed that the expression of Notch-resistant E2A and constitutively active STAT5 in mice neutralized the effects of Notch-induced degradation, allowing B-cell development through a bone marrow-like program in the thymus. These findings illustrate that Notch function can be influenced by MAPKs, producing distinct outcomes in different cellular contexts.

Published ahead of print on 14 January 2008.