Regulation of lymphocyte development by cell-type-specific interpretation of Notch signals.

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.