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  • The EMBO Journal (2007) 26, 1670 - 1680
  • doi:10.1038/sj.emboj.7601626

Published online: 1 March 2007

Notch3 and the Notch3-upregulated RNA-binding protein HuD regulate Ikaros alternative splicing

Diana Bellavia1, Marco Mecarozzi1, Antonio F Campese1, Paola Grazioli1, Claudio Talora1, Luigi Frati2, Alberto Gulino1,2 and Isabella Screpanti1,3

  1. Department of Experimental Medicine, University 'La Sapienza', Roma, Italy
  2. Neuromed Institute, Pozzilli, Italy
  3. Istituto Pasteur-Fondazione Cenci Bolognetti, University 'La Sapienza', Roma, Italy

Correspondence to:

Isabella Screpanti, Laboratory of Molecular Pathology, Dipartimento di Medicina Sperimentale, University 'La Sapienza', Viale Regina Elena 324, Roma 00161, Italy. Tel.: +39 06 44700816; Fax: +39 06 4464129; E-mail: isabella.screpanti@uniroma1.it

Received 20 July 2006; Accepted 5 February 2007

Constitutive activation of the transmembrane receptor, Notch3, and loss of function of the hematopoietic transcription repressor, Ikaros (IK), play direct roles in T-cell differentiation and leukemogenesis that are dependent on pre-T-cell receptor (pre-TCR) signaling. We demonstrate the occurrence of crosstalk between Notch3 and IK that results in transcriptional regulation of the gene encoding the pTalpha chain of the pre-TCR. We also show that, in the presence of the pre-TCR, constitutive activation of Notch3 in thymocytes causes increased expression of dominantnegative non-DNA-binding IK isoforms, which are able to restrain the IK inhibition of Notch3's transcriptional activation of pTalpha. This effect appears to be mediated by Notch3's pre-TCR-dependent upregulation of the RNA-binding protein, HuD. Notch3 signaling thus appears to play a critical role in the diminished IK activity described in several lymphoid leukemias. By exerting transcription-activating and transcription-repressing effects on the pTalpha promoter, Notch3 and IK cooperate in the fine-tuning of pre-TCR expression and function, which has important implications for the regulation of thymocyte differentiation and proliferation.

  • Keywords:

    • alternative splicing,
    • Ikaros,
    • Notch3,
    • pre-TCR,
    • T-cell leukemia