Abstract
ABSTRACTGli3 is a Hedgehog (Hh)-responsive transcription factor that can function as a transcriptional repressor or activator. We show that Gli3 activity in mouse thymic epithelial cells (TECs) promotes positive selection and differentiation from CD4+ CD8+ to CD4+ CD8− single-positive (SP4) cells in the fetal thymus and that Gli3 represses Shh. Constitutive deletion of Gli3, and conditional deletion of Gli3 from TECs, reduced differentiation to SP4, whereas conditional deletion of Gli3 from thymocytes did not. Conditional deletion of Shh from TECs increased differentiation to SP4, and expression of Shh was upregulated in the Gli3-deficient thymus. Use of a transgenic Hh reporter showed that the Hh pathway was active in thymocytes, and increased in the Gli3-deficient fetal thymus. Neutralisation of endogenous Hh proteins in the Gli3−/− thymus restored SP4 differentiation, indicating that Gli3 in TECs promotes SP4 differentiation by repression of Shh. Transcriptome analysis showed that Hh-mediated transcription was increased whereas TCR-mediated transcription was decreased in Gli3−/− thymocytes compared with wild type.
Highlights
Gli3 is a member of the Hedgehog (Hh)-responsive Gli family of transcription factors, mammalian orthologues of the Drosophila Ci protein (Ramsbottom and Pownall, 2016)
Impaired development of mature SP4 T-cells in the Gli3 mutant thymus Gli3 deficiency is embryonic lethal, so to investigate whether Gli3 is required for differentiation of thymocytes from the DP to SP stage, we cultured wild-type (WT) and Gli3 mutant E17.5 mouse fetal thymus organ culture (FTOC) for 4 days and assessed changes in developmentally regulated cell-surface markers
Here, we showed that expression of the transcription factor Gli3 in thymic epithelial cells (TECs) is necessary for normal differentiation from DP to mature SP4 thymocyte in the fetal thymus
Summary
Gli is a member of the Hedgehog (Hh)-responsive Gli family of transcription factors, mammalian orthologues of the Drosophila Ci protein (Ramsbottom and Pownall, 2016). Gli can be processed to be a repressor of transcription (Gli3R) in the absence of Hh signalling, or an activator (Gli3A) upon Hh signal transduction (Sasaki et al, 1999). During development it can function before the expression of Hh genes, independently of Hh. In many tissues, Gli3R limits Shh signalling, Gli3R and Shh have opposing functions, and Gli deficiency and Shh deficiency result in opposite phenotypes (Hager-Theodorides et al, 2005; Shah et al, 2004; Solanki et al, 2017; te Welscher et al, 2002; Wang et al, 2000).
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