Smoothened function in T cell development

The thymus gland plays an essential role in immunological protection against infection by supporting the production of T cells, a type of white blood cell. T cells are an important constituent of the immune system, that enable us to fight infection, and also regulate other types of cell, preventing our immune system from attacking our own bodies. An understanding of how T cells are produced will help us to understand how they function and will be useful in designing treatments for human disease. This project will study molecules that are involved in the regulation of T cell production the thymus. In particular, we will investigate the functions of a molecule called Smoothened in the production of T cells and other types of blood cell. Smoothened is known to be a very important molecule during the embryonic development of many tissues and organs, such as the heart and bone, but little is known about its functions in the production of T cells and other blood cells. This project will take a genetic approach to study the functions of Smoothened. We will ask what effect mutations in the gene that encodes Smoothened have on the production of T cells in the thymus, and on the projection of other types of blood cell.

The thymus, the primary site of T cell production, is seeded throughout life by blood borne progenitor cells from the foetal liver or adult bone marrow. This project aims to investigate the function of the Hedgehog (Hh) pathway signal transduction molecule Smoothened (Smo) in the regulation of haematopoiesis and thymopoesis. The Hh family of secreted intercellular signalling molecules are powerful regulators of patterning and organogenesis of many mammalian tissues during embryonic development, but relatively little is known about the function of Hh signalling in the immune system. We will focus on the signal transduction molecule Smo to avoid the complications of redundancy created by multiple mammalian Hh family members and down-stream transcription factor (GIi) family members. We will use conditional Smo Knock-out mice to study the function of Hh signalling in haematopoietic stem cells and lymphocyte progenitor cells as they seed the thymus and develop down the T cell lineage. Conversely, we will generate transgenic mice in which Smo is constitutively active in haematopoietic and lymphocyte lineage cells. We will test the hypothesis that Smo is an important regulator of haematopoiesis and lymphocyte development. We aim to define the functions of Smo during T cell development and to elucidate the molecular mechanisms that underlie these functions, identifying genes that are transcriptionally regulated by Smo signalling.