Lau, CI; (2014) Hedgehog Signalling in Haematopoiesis. Doctoral thesis , UCL (University College London).

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Abstract

The Hedgehog (Hh) family proteins and their signalling pathway are key mediators of, and important in, many mammalian developmental processes. Malfunction of the Hh signalling pathway contributes to developmental disorders and birth defects. This project aims to investigate the role of the Hh signalling pathway in murine haematopoiesis. In our study, we found that Dhh plays a negative regulatory role in normal erythropoiesis and under stress conditions. However, it is not required for regulating erythropoiesis in the fetal liver during embryo development. In contrast, analysis of conditional deletion of Smo in haematopoietic cells revealed that Smo controls early haematopoietic differentiation in the fetal liver but is dispensable for regulating haematopoiesis in adult bone marrow and spleen. Furthermore, pervious studies have demonstrated that Hh signalling is involved in T-cell development throughout maturation. We tested the hypothesis that Foxa2, a downstream target gene of Hh during pre-TCR signalling, is also required for late T-cell development and activation. Analysis of mice conditionally Foxa2-deficient in mature T-cells revealed that Foxa2 is important in the process of maturation in late thymocyte development. In addition, Foxa2 is also involved in regulation of T-cell activation, and the differentiation of T helper cells. Gene expression experiments confirmed that Foxa2 is also a Hh target gene in the thymus. Taken together, our findings revealed that the Hh signalling pathway and its target genes play critical roles in haematopoiesis during embryogenesis and in adult mice.

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