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 Blood, 21 May 2009, Vol. 113, No. 21, pp. 5144-5156.
Prepublished online as a Blood First Edition Paper on March 9, 2009; DOI 10.1182/blood-2008-10-185751.

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Submitted October 27, 2008
Accepted March 6, 2009

Sonic hedgehog negatively regulates pre-TCR induced differentiation by a Gli2 dependent mechanism

Nicola J. Rowbotham, Ariadne L. Hager-Theodorides, Anna L. Furmanski, Susan E. Ross, Susan V. Outram, Johannes T. Dessens, and Tessa Crompton*

Immunobiology Unit, UCL Institute of Child Health, London, United Kingdom
Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom

* Corresponding author; email: t.crompton{at}ich.ucl.ac.uk.

Hedgehog signaling regulates differentiation, survival and proliferation of the earliest DN thymocytes, but its importance at later stages of T-cell development is controversial. Here we use loss- and gain-of-function mouse models to show that Shh, by signaling directly to the developing thymocyte, is a negative regulator of pre-TCR induced differentiation from DN to DP cell. When Hedgehog signaling was reduced, in the Shh-/- and Gli2-/- thymus, or by T-lineage specific transgenic expression of a transcriptional-repressor form of Gli2 (Gli2{Delta}C2), differentiation to DP cell after pre-TCR signal transduction was increased. In contrast, when Hh signaling was constitutively activated in thymocytes, by transgenic expression of a constitutive transcriptional-activator form of Gli2 (Gli2{Delta}N2), the production of DP cells was decreased. Gene expression profiling showed that physiological Hh signaling in thymocytes maintains expression of the transcription factor FoxA2 on pre-TCR signal transduction.


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A. L. Hager-Theodorides, A. L. Furmanski, S. E. Ross, S. V. Outram, N. J. Rowbotham, and T. Crompton
The Gli3 Transcription Factor Expressed in the Thymus Stroma Controls Thymocyte Negative Selection Via Hedgehog-Dependent and -Independent Mechanisms
J. Immunol., September 1, 2009; 183(5): 3023 - 3032.
[Abstract] [Full Text] [PDF]


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