Biomedical Science
http://hdl.handle.net/10547/556922
2024-03-16T02:29:55ZSonic Hedgehog regulates thymic epithelial cell differentiation
http://hdl.handle.net/10547/604700
Sonic Hedgehog regulates thymic epithelial cell differentiation
Saldaña, José Ignacio; Solanki, Anisha; Lau, Ching-In; Sahni, Hemant; Ross, Susan; Furmanski, Anna L.; Ono, Masahiro; Holländer, Georg; Crompton, Tessa
Sonic Hedgehog (Shh) is expressed in the thymus, where it regulates T cell development. Here we investigated the influence of Shh on thymic epithelial cell (TEC) development. Components of the Hedgehog (Hh) signalling pathway were expressed by TEC, and use of a Gli Binding Site-green fluorescence protein (GFP) transgenic reporter mouse demonstrated active Hh-dependent transcription in TEC in the foetal and adult thymus. Analysis of Shh-deficient foetal thymus organ cultures (FTOC) showed that Shh is required for normal TEC differentiation. Shh-deficient foetal thymus contained fewer TEC than wild type (WT), the proportion of medullary TEC was reduced relative to cortical TEC, and cell surface expression of MHC Class II molecules was increased on both cortical and medullary TEC populations. In contrast, the Gli3-deficient thymus, which shows increased Hh-dependent transcription in thymic stroma, had increased numbers of TEC, but decreased cell surface expression of MHC Class II molecules on both cortical and medullary TEC. Neutralisation of endogenous Hh proteins in WT FTOC led to a reduction in TEC numbers, and in the proportion of mature Aire-expressing medullary TEC, but an increase in cell surface expression of MHC Class II molecules on medullary TEC. Likewise, conditional deletion of Shh from TEC in the adult thymus resulted in alterations in TEC differentiation and consequent changes in T cell development. TEC numbers, and the proportion of mature Aire-expressing medullary TEC were reduced, and cell surface expression of MHC Class II molecules on medullary TEC was increased. Differentiation of mature CD4 and CD8 single positive thymocytes was increased, demonstrating the regulatory role of Shh production by TEC on T cell development. Treatment of human thymus explants with recombinant Shh or neutralising anti-Shh antibody indicated that the Hedgehog pathway is also involved in regulation of differentiation from DP to mature SP T cells in the human thymus.
2016-01-01T00:00:00ZTissue-derived hedgehog proteins modulate Th differentiation and disease
http://hdl.handle.net/10547/604697
Tissue-derived hedgehog proteins modulate Th differentiation and disease
Furmanski, Anna L.; Saldaña, José Ignacio; Ono, Masahiro; Sahni, Hemant; Paschalidis, Nikolaos; D'Acquisto, Fulvio; Crompton, Tessa
Genome-wide association studies of complex immune-mediated diseases have indicated that many genetic factors, each with individual low risk, contribute to overall disease. It is therefore timely and important to characterize how immune responses may be subtly modified by tissue context. In this article, we explore the role of tissue-derived molecules in influencing the function of T cells, which, owing to their migratory nature, come into contact with many different microenvironments through their lifespan. Hedgehog (Hh) proteins act as secreted morphogens, providing concentration-dependent positional and temporal cell-fate specification in solid tissues. Hh signaling is required for embryogenesis and is important in postnatal tissue renewal and in malignancy. However, the function of Hh in dynamic, fluid systems, such as in mammalian immunity, is largely unknown. In this article, we show that Hh-dependent transcription in T cells promoted Th2 transcriptional programs and differentiation, exacerbating allergic disease. Of interest, expression of Sonic Hh increased in lung epithelial cells following the induction of allergic disease, and lung T cells upregulated Hh target gene expression, indicating that T cells respond to locally secreted Hh ligands in vivo. We show that Il4, the key Th2 cytokine, is a novel transcriptional target of Hh signals in T cells, providing one mechanism for the role of Hh in Th differentiation. We propose that Hh, secreted from inflamed, remodeling, or malignant tissue, can modulate local T cell function. Our data present an unexpected and novel role for tissue-derived morphogens in the regulation of fluid immune responses, with implications for allergy and tumor responses, suggesting new uses for anti-Hh therapeutics.
2013-02-13T00:00:00ZHaemophilia A and cardiovascular morbidity in a female SHAM syndrome carrier due to skewed X chromosome inactivation
http://hdl.handle.net/10547/595147
Haemophilia A and cardiovascular morbidity in a female SHAM syndrome carrier due to skewed X chromosome inactivation
Janczar, Szymon; Kosinska, Joanna; Ploski, Rafal; Pastorczak, Agata; Wegner, Olga; Zalewska-Szewczyk, Beata; Paige, Adam J.W.; Borowiec, Maciej; Mlynarski, Wojciech
We have recently described a severe haemophilia A and moyamoya (SHAM) syndrome caused by Xq28 deletions encompassing F8 and the BRCC3 familial moyamoya gene. The phenotype includes haemophilia A, moyamoya angiopathy, dysmorphia and hypertension. The genetic analysis of the family of our SHAM patient demonstrated carrier state in proband's mother and sister. The patient's mother is apparently well, whereas his currently 18-years-old sister presents with mild haemophilia A, coarctation of the aorta, hypertension, and ventricular arrhythmia. We performed X chromosome inactivation assay based on HpaII methylation analysis of a polymorphic short tandem repeat (STR) in the X linked AR (androgen receptor) gene and used quantitative real-time RT PCR to measure the expression of genes from the deleted region in proband's family members. We found an extremely skewed X chromosome inactivation pattern in the female members of the family leading to preferential inactivation of the X chromosome without Xq28 deletion in patient's sister. We demonstrated differential expression of the genes from the deleted region in four members of the family, that tightly correlates with the clinical features. In conclusion, we show that the haematologic and cardiovascular morbidity and the discrepancy between patient's sister and mother despite the same genetic lesion are due to skewed X chromosome inactivation leading to clinically relevant differential expression of SHAM syndrome genes. This report highlights the role for BRCC3 in cardiovascular physiology and disease, and demonstrates that in some complex hereditary syndromes full diagnostics may require the examination of both genetic and epigenetic events.
2016-01-01T00:00:00ZGli2, hedgehog and TCR signalling
http://hdl.handle.net/10547/581938
Gli2, hedgehog and TCR signalling
Furmanski, Anna L.; Crompton, Tessa
Editorial
2015-07-01T00:00:00Z