The SOX Switch

RESEARCH HIGHLIGHTS

DOI: 10.1038/nri2044

URLs SOX13 http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?db=gene&c md=Retrieve&dopt=full_ report&list_uids=9580 T-CELL DEVELOPMENT The SOX switch

diversion, Melichar et al. screened of cell division and inhibit the for transcription factors that were proliferative burst associated with differentially expressed by αβ and γδ the transition of αβ-lineage cells thymocytes and identified SOX13 from the TN to the double-positive as a γδ-lineage-restricted molecule. (CD4+CD8+) stage. Sox13 gene expression was shown Analysis of gene-expression to be highest in TN1 and TN2 cells profiles revealed that overexpression — developmental stages imme- of SOX13 in αβ-lineage T cells led diately prior to the expression of to the induction of expression of the pre-T-cell receptor (pre-TCR) the TCR γ-chain, which is normally by thymocytes that are otherwise repressed in these cells by the destined to become αβ T cells — and transcription factor T-cell factor 1 was subsequently turned off from (TCF1) downstream of WNT the TN3 stage onwards in developing signalling. Interestingly, the phe- αβ-lineage cells. Single-cell analysis notype of Sox13-transgenic mice revealed that Sox13 was expressed is similar to that of TCF1-deficient in 46% of TN2 cells, which indicates mice. So the authors tested the that this population is heterogeneous. possibility that SOX13 functions Expression of Sox13 before pre-TCR by antagonizing TCF1. Indeed, expression indicates that some SOX13 could inhibit expression lineage commitment has already of a reporter gene controlled by αβ and γδ T cells have distinct func- occurred at the TN2 stage. TCF1-binding sites in an artificial tions and reside in different locations To probe the function of SOX13 promoter and expression driven by yet they originate from a common in determining cell fate, the authors the Ly49a promoter, a known TCF1 precursor in the thymus. So what generated transgenic mice that target. This inhibitory effect might determines one cell fate over another? overexpressed SOX13 in thymocyte be mediated by direct binding of Addressing this issue, Melichar et al. precursors and SOX13-deficient SOX13 to TCF1. identify SOX13 as a γδ-lineage-spe- mice. The transgenic mice had sig- This study identifies SOX13 as the cific transcription factor. nificantly fewer αβ-lineage T cells first γδ-lineage-specific transcription Progenitors for both αβ and γδ compared with littermate controls, factor that seems to function as a T cells enter the thymus as triple- whereas γδ T cells developed switch to control γδ- versus αβ-T-cell negative (TN; CD3–CD4–CD8–) normally, which is consistent with development, in part, by controlling cells and proceed through a series a role for SOX13 in antagonizing TCF1 activity. of discrete stages before becoming αβ-T-cell development. By contrast, Lucy Bird mature T cells. γδ-T-cell differen- SOX13-deficient mice showed γδ tiation is thought to diverge from defects in -T-cell development, ORIGINAL RESEARCH PAPER Melichar, H. J. αβ-T-cell development between the but not αβ-T-cell development. The et al. Regulation of γδ versus αβ T lymphocyte TN2 and TN4 stages. To determine authors noted that SOX13 might differentiation by the transcription factor SOX13. Science 315, 230–233 (2007) what might control this lineage function as a negative regulator