Stem cells must proliferate and differentiate to generate the lineages that shape mature organs; understanding these 2 processes and their interaction is one of the central themes in current biomedicine. An intriguing aspect is asymmetric division, by which 2 daughter cells with different fates are generated. Several cell fate determinants participate in asymmetric division, with the endocytic adaptor Numb as the best-known example. Here, we have explored the role of asymmetric division in thymocyte development, visualizing the differential segregation of Numb and pre-TCR in thymic precursors. Analysis of mice where Numb had been inhibited by expressing a dominant negative revealed enhanced pre-T-cell receptor (TCR) signaling and a smaller thymus. Conversely, Numb overexpression resulted in loss of asymmetric division and a larger thymus. The conclusion is that Numb determines the levels of pre-TCR signaling in dividing thymocytes and, ultimately, the size of the pool from which mature T lymphocytes are selected. IntroductionThe mammalian thymus contains different cell types originated from initially equivalent precursors that undergo several rounds of division. To ensure correct numbers of mature lineage-specific cells in adult organs, precursors divide asymmetrically, generating 2 sister cells with different fates. 1,2 One of the "cell fate determinants" asymmetrically segregated is Numb, a plasma membrane-associated protein that contains a phosphotyrosine binding (PTB) domain and antagonizes Notch signaling. Numb function was first described in Drosophila sensory organ precursors, 3 where loss of Numb resulted in both daughter cells adopting the fate of the cell that normally inherits Notch, whereas the opposite was caused by Numb overexpression. [4][5][6] In mammalians, asymmetric division has been studied most extensively during neurogenesis. 7 Deletion of Numb and its homologue Numblike resulted in loss of neural progenitors and block of neurogenesis, 8 as a result of progenitor overdifferentiation and death of young neurons. In other systems, Numb binds to integrins 9 and Src family kinases, 10 mediates receptor internalization, 11,12 and participates in clathrin-dependent endosomal association. 13 Thus, Numb plays multiple and important roles in development and signaling; however, little is known about its role in the thymus.T lymphocytes develop from precursors that undergo a series of cell fate decisions, resulting in differentiation into single positive (SP) thymocytes, the immediate precursors of fully functional CD4 and CD8 T lymphocytes. 14,15 The initial CD4 Ϫ CD8 Ϫ double negative (DN) stages are influenced by signals from the pre-T-cell receptor (TCR) [16][17][18] and Notch. 19,20 Only DN thymocytes receiving proper pre-TCR and Notch signals are able to evolve into the CD4 ϩ CD8 ϩ double positive (DP) ␣ lineage stage. Pre-TCR internalization and degradation is very important for correct signaling. [21][22][23] As a consequence of pre-TCR signaling, DN thymocytes proliferate, enabling normal nu...
Modulation of TCR signaling upon ligand binding is achieved by changes in the equilibrium between TCR degradation, recycling and synthesis; surprisingly, the molecular mechanism of such an important process is not fully understood. Here, we describe the role of a new player in the mediation of TCR degradation: the endocytic adaptor Numb. Our data show that Numb inhibition leads to abnormal intracellular distribution and defective TCR degradation in mature T lymphocytes. In addition, we find that Numb simultaneously binds to both Cbl and a site within CD3ε that overlaps with the Nck binding site. As a result, Cbl couples specifically to the CD3ε chain to mediate TCR degradation. The present study unveils a novel role of Numb that lies at the heart of TCR signaling initiation and termination.
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