Centro Nacional de Biotecnología/CSIC, Spain
Carlos Martínez-A is Professor of Immunology at the Centro Nacional de Biotecnología (CNB)/CSIC in Madrid, Spain. He has worked at the Basel Institute for Immunology, Basel, the School of Medicine at Umea, Sweden, and the Institute Pasteur, France. He has spent sabbatical periods at several institutions, including the Ontario Cancer Institute, Caltech and the Max Planck Institute in Freiburg. He has chaired the European Molecular Biology Conference, the starting grants call in 2007 and the Synergy Grants in 2012-13 of the ERC, and served at the HSFP, ESF, EUROHORCS and EMBO Council. He served as President of the CSIC from 2004 to 2008, and was appointed Secretary of State for Research (2008-2009). He has publish more than 450 paper, he is a member of EMBO, the Academia Europeae and several professional academies and has received the distinction of Doctor honoris causa from several universities. His main field of research is immunology, autoimmune diseases and more recently, stem cells and immunity.
Genome-wide screens have identified numerous potential regulators of stem cell function. These include genes with established roles in transcription regulation, cell growth and differentiation, as well as those whose function is largely unknown or remains to be validated, such as Dido (death inducer-obliterator). We identified Dido, a gene complex that encodes three proteins (Dido1, Dido2 and Dido3) generated through alternative splicing. The largest isoform, Dido3, is expressed ubiquitously, whereas the two smaller splice variants can be detected only transiently. Bioinformatics analysis of Dido3 composition suggests a role in the maintenance of genomic stability. Dido3 comprises a plant homeodomain (PHD) finger, a transcription elongation factor S-II subunit M (TFSIIM) domain, a Spen paralogue and orthologue (SPOC) module, an Helical Bimodular (HBM) domain, and long C-terminal region (CT) of unknown homology. Misregulation of the Dido gene is linked to increased incidence of genomic instability, myelodysplasia and myeloproliferation, melanoma and infertility. Elimination of the Dido gene in mice causes early embryonic lethality. We generated Dido mouse mutants in which the Dido3 C-terminal region (Dido3CT) was deleted during development by the Cre system under the Sox promoter (Dido3-loxP-GFP), or was replaced with a red fluorescent protein tag (Dido3CT-RFP). Although withdrawal of LIF (leukemia inhibitory factor) led to stem cell differentiation in Wt/Wt embryonic bodies, stem cells from the Dido3-loxP-GFP or the Dido3CT-RFP mutants did not differentiate, whereas they maintained self renewal capacity. Differentiation was restored by ectopic expression of Wt Dido3 and constructs bearing different Dido domains. Our results show a role for the Dido PHD and HBM domains in regulating self renewal and stem cell differentiation.