Abstract
Numb asymmetrically segregates at mitosis to control cell fate choices during development. Numb inheritance specifies progenitor over differentiated cell fates, and, paradoxically, also promotes neuronal differentiation, thus indicating that the role of Numb may change during development. Here we report that Numb nuclear localization is restricted to early thymocyte precursors, whereas timed appearance of pre-T-cell receptor (pre-TCR) and activation of protein kinase Cθ promote phosphorylation-dependent Numb nuclear exclusion. Notably, nuclear localization of Numb in early thymocyte precursors favors p53 nuclear stabilization, whereas pre-TCR-dependent Numb nuclear exclusion promotes the p53 downmodulation essential for further differentiation. Accordingly, the persistence of Numb in the nucleus impairs the differentiation and promotes precursor cell death. This study reveals a novel regulatory mechanism for Numb function based on its nucleus–cytosol shuttling, coupling the different roles of Numb with different stages of T-cell development.
Highlights
Numb is essential for maintaining the progenitors during the initial progenitor versus neural fate decision.[4,5] re-expression of Numb is required for further neural differentiation,[6,7] indicating that the role of Numb in the same tissue may change over time
We focused our attention on the DN3 stage of thymocyte development, as we previously reported that DN3 development is dependent on Numb function.[11]
The presence and function of pre-T-cell receptor (pre-TCR) signaling at DN3 stage, by promoting the nuclear exclusion of Numb, is responsible of the p53 downmodulation, necessary to allow the survival of DN3 thymocytes, and to continue their differentiation (Figure 7)
Summary
Numb is essential for maintaining the progenitors during the initial progenitor versus neural fate decision.[4,5] re-expression of Numb is required for further neural differentiation,[6,7] indicating that the role of Numb in the same tissue may change over time. Numb function in the immune system has been partially explored.[8,9] Numb is involved in asymmetric division in hematopoietic stem cells,[10] thymocytes[11] and mature T lymphocytes.[12,13] T cells develop from intrathymic CD4−CD8−. Recent data describe the presence of Numb in the nuclear compartment,[23] besides its known cytoplasmic localization, raising the possibility that different Numb functions could be regulated by its differential subcellular localization. Whether Numb may have different subcellular localizations in precursors or more differentiated T cell, how Numb import is regulated or how the nuclear localization affects its function during T-cell development remain unexplored.
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