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Prepublished online as a Blood First Edition Paper on June 26, 2003; DOI 10.1182/blood-2002-10-3261.
Submitted October 28, 2002
Accepted June 9, 2003
Sustained notch1 signaling instructs the earliest human intrathymic precursors to adopt a   T cell fate in fetal thymus organ culture
Marina Garcia-Peydro, Virginia G de Yebenes, and Maria L Toribio*
Centro de Biologia Molecular Severo Ochoa. CSIC., Madrid, Spain
* Corresponding author; email: mtoribio{at}cbm.uam.es.
Notch1 activity is essential for the specification of T lineage fate in hematopoietic progenitors. Once the T-cell lineage is specified, T cell precursors in the thymus must choose between   and   lineages. However, the impact of Notch1 signaling on intrathymic pro-T cells has not been addressed directly. To approach this issue, we used retroviral vectors to express constitutively active Notch1 in human thymocyte progenitors positioned at successive developmental stages, and we followed their differentiation in fetal thymus organ culture (FTOC). Here we show that sustained Notch1 signaling impairs progression to the DP stage and efficiently diverts the earliest thymic progenitors from the main T cell pathway toward development of T cells. The impact of Notch1 signalling on skewed production decreases progressively along intrathymic maturation and is restricted to precursor stages upstream of the pre-TCR checkpoint. Close to and beyond that point, Notch1 is no further able to instruct cell fate, but promotes an abnormal expansion of -committed thymocytes. These results stress the stage-specific impact of Notch1 signaling in intrathymic differentiation and suggest that regulation of Notch1 activity at defined developmental windows is essential to control versus T cell development and to avoid deregulated expansion of -lineage cells.
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