Regulation of lymphocyte development by cell-type-specific interpretation of notch signals

Lei Nie, S. Scott Perry, Ying Zhao, Jiaxue Huang, Paul W. Kincade, Michael A. Farrar, Xiao Hong Sun

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2078-2090
Number of pages13
JournalMolecular and cellular biology
Issue number6
StatePublished - Mar 2008

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