ERC FUNDED PROJECTS

The discovery of adult neural stem cells (NSCs) has broaden our view of the physiological plasticity of the nervous system, and has opened new perspectives on the possibility of tissue regeneration and repair in the brain. NSCs reside in specialized niches in the adult mammalian nervous system, where they are exposed to specific paracrine signals regulating their behavior. These neural progenitors are generally in a quiescent state within their niche, and they activate their proliferation depending on tissue regenerative and growth needs. Understanding the mechanisms by which NSCs enter and exit the quiescent state is crucial for the comprehension of the physiology of the adult nervous system. In this project we will study the behavior of a specific subpopulation of adult neural stem cells recently described by our group in the carotid body (CB). This small organ constitutes the most important chemosensor of the peripheral nervous system and has neuronal glomus cells responsible for the chemosensing, and glia-like sustentacular cells which were thought to have just a supportive role. We recently described that these sustentacular cells are dormant stem cells able to activate their proliferation in response to a physiological stimulus like hypoxia, and to differentiate into new glomus cells necessary for the adaptation of the organ. Due to our precise experimental control of the activation and deactivation of the CB neurogenic niche, we believe the CB is an ideal model to study fundamental questions about adult neural stem cell physiology and the interaction with the niche. We propose to study the cellular and molecular mechanisms by which these carotid body stem cells enter and exit the quiescent state, which will help us understand the physiology of adult neurogenic niches. Likewise, understanding this neurogenic process will improve the efficacy of using glomus cells for cell therapy against neurological disease, and might help us understand some neural tumors.

1 476 000 €

Start date: 2010-11-01, End date: 2015-10-31

The majority of animals show an external bilateral symmetry, precluding the observation of multiple internal left-right (L/R) asymmetries which are fundamental for organ packaging and function. A prominent molecular pathway converging on and downstream of the Pitx2 transcription factor confers left-handed information in the left side of the embryo, with players expressed on the right ensuring that the left determinants are excluded. Therefore, conferring or excluding left identity in left and right hand sides, respectively, drives L/R asymmetry. Some indications suggest that a program actively specifying right–handed information could exist on the right. Our recent findings support this view. In a screening for novel regulators of the epithelial to mesenchymal transition (EMT), we have identified a transcription factor, EMT2, which similarly to well known factor Snail, it is an EMT inducer. The EMT is crucial for the development of tissues during embryonic development and for the progression of carcinomas to the invasive state. Strikingly, again as Snail, in addition to promote EMT, the EMT2 factor is predominantly expressed on the right side and may operate instructing L/R identity on the right-hand side of the embryo. With this background, our knowledge of the EMT and a series of genome-wide high-throughput approaches and a comprehensive functional analysis using the chick, the fish and the mouse as model systems we propose to reveal the putative molecular pathways conveying right-handed information and to reveal commonalities between L/R pathways and the EMT. In the long run, we aim at better understanding human pathologies that involve these morphogenetic and cellular processes, including pathological situs conditions (i.e. altered organ positioning) and cancer progression.

2 460 000 €

Start date: 2013-05-01, End date: 2018-12-31

Gadd45 family proteins play a critical role in genomic stability, cell cycle regulation proliferation and apoptosis. Gadd45a is activated by the tumor suppressor gene p53, which is mutated in >50% of human tumors. The lack of GADD45a in mice leads to spontaneous development of an autoimmune disease similar to systemic lupus erythematosus. The molecular mechanisms that cause autoimmunity are poorly understood. Recent evidence suggests that p38 activation is involved in autoimmune development and tumor suppression. We found that Gadd45a negatively regulates p38 activity in T cells by preventing phosphorylation on Tyr323. Inhibition of Tyr323p38 phosphorylation is a potential therapeutic target in several types of leukemia and autoimmune diseases, including lupus and rheumatoid arthritis. The main goals of this project are a) to study the in vivo function of the Gadd45 family and p38 in tumor suppression and autoimmunity, and b) to analyze their molecular mechanisms to identify targets for disease treatment. We will dissect the signaling pathways involved in development of autoimmunity and cancer using a multidisciplinary approach that combines mouse genetic, human epigenetic, biochemical, molecular biological and immunological techniques. Our project involves the characterization of murine models deficient in each member of the Gadd45 family (Gadd45a, Gadd45b, Gadd45g), as well as double- and triple-knockout mice, development of a knock-in model for p38a, in vivo and in vitro analysis of T cell activation, proliferation, apoptosis and differentiation, epigenetic studies of potential targets, and finally, validation of these results in autoimmune disease and cancer patients. The results of this project will help identify new therapeutic targets for autoimmune diseases and/or cancer.

1 755 805 €

Start date: 2008-09-01, End date: 2014-08-31

Accurate partitioning of the genetic material during cell division is critical for genetic stability. Defects in chromosome segregation produce aneuploidy, an unequal distribution of chromosomes between daughter cells, which is cause of developmental defects, and one of the cancer hallmarks. To ensure error-free transmission of chromosomes, feedback control systems verify that processes at each stage of the cycle have been completed before progression into the next stage. In particular, the spindle assembly checkpoint prevents initiation of anaphase until chromosomes attach properly to the spindle, whereas the NoCut checkpoint, which I identified, delays cytokinesis until chromosome segregation is complete. The discovery of NoCut, which is conserved from yeast to humans, reveals that eukaryotic cells monitor chromosome segregation during anaphase. The molecular mechanisms of this, and potentially other anaphase feedback controls remain obscure. The goal of this proposal is to achieve a detailed understanding of the mechanisms coordinating chromosome segregation and cytokinesis. Key to this task will be the experimental manipulation of chromosome architecture in budding yeast, which allows the generation of cells with extra long chromosome arms. Using this strategy, we have already uncovered one novel feedback system, which monitors axial chromosome compaction during anaphase. We will investigate this and other anaphase controls through a multidisciplinary approach, which combines genetic techniques with state-of-the-art live cell microscopy, genomics and proteomics. We will characterize the feedback mechanism controlling chromosome compaction, and the molecular basis of chromosome segregation errors during anaphase. The relevance of these novel processes will be confirmed by analysis of cell division in animal cells and in a Drosophila tumour model. These approaches will advance our understanding of how eukaryotic cells prevent aneuploidy and tumorigenesis.

1 058 610 €

Start date: 2011-06-01, End date: 2017-05-31