Objective There is growing evidence that molecules classically allocated to nervous system function, such as the neurotrophic factors, are produced by lymphocytes and can also regulate their function. The neurotrophic family includes the GDNF ligands (GFLs), which signal through the RET tyrosine kinase receptor. In humans, mutations of the proto-oncogene Ret have been linked to different diseases, such as cancer and Hirschsprung’s disease. Interestingly, RET expression has been reported in lymphocytes but its functional significance is unclear. We propose to use combined genetic, cellular, and molecular approaches in order to determine, quantify and manipulate the function of RET and GFLs during haematopoiesis and lymphocyte differentiation. In order to achieve this, we will analyse the patterns of RET and GFL expression during haematopoiesis, and in mature lymphocyte sub-sets. By using this strategy we aim to identify differentiation stages where the Ret exerts its role. We then plan to assess the functions of RET and candidate GFLs by studying the impact of Ret and GFL gene ablation. To achieve this, we will study lymphoid cells at different stages of differentiation from mice deficient for Ret or GFLs, and determine the role that these molecules play in key cellular and molecular events during haematopoiesis and immune responses. Since RET is likely to exert its function at various differentiation steps, we plan to use genetically modified mice allowing the conditional deletion of Ret. As a complementary approach, we will generate mice over-expressing RET or constitutively activated RET in a tissue-specific manner, thus mimicking activating mutations of RET associated with cancer. We believe our work, apart from its novelty in the field of immunology, will have a broader impact in other disciplines. Indeed, mechanisms historically ascribed to a specific tissue may be used more generally in order to orchestrate the function and communication among different systems. Fields of science natural sciencesbiological sciencesneurobiologymedical and health sciencesbasic medicineimmunologynatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncology Keywords Genetically modified mice Lymphocyte differentiation Neurotrophic factors Proto-oncogenes Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-SG-LS3 - ERC Starting Grant - Cellular and Developmental Biology Call for proposal ERC-2007-StG See other projects for this call Funding Scheme ERC-SG - ERC Starting Grant Coordinator INSTITUTO DE MEDICINA MOLECULAR JOAO LOBO ANTUNES Address Avenida prof egas moniz 1649 028 Lisboa Portugal See on map Region Continente Área Metropolitana de Lisboa Área Metropolitana de Lisboa Activity type Research Organisations Administrative Contact Maria Do Carmo Fonseca (Prof.) Principal investigator Jose Henrique Veiga Fernandes (Dr.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution € 1 901 400,00 Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all INSTITUTO DE MEDICINA MOLECULAR JOAO LOBO ANTUNES Portugal EU contribution € 1 901 400,00 Address Avenida prof egas moniz 1649 028 Lisboa See on map Region Continente Área Metropolitana de Lisboa Área Metropolitana de Lisboa Activity type Research Organisations Administrative Contact Maria Do Carmo Fonseca (Prof.) Principal investigator Jose Henrique Veiga Fernandes (Dr.) Links Contact the organisation Opens in new window Website Opens in new window
