Department and institution: Department of Biotechnology and Biosciences - University of Milano Bicocca
Keywords: gene regulation, mouse genetic models, neural stem cells, neurogenesis, transcription factors
Sox2 is a transcription factor essential for pluripotent stem cells, also active in stem cells of different tissues. Our group investigates the role of Sox2 in the development of the nervous system, in particular of the brain, analysing the molecular mechanisms of its action. In parallel, we also study the possible role of Sox2 in brain tumors. One aim of our studies is to better understand, through the functional investigation of Sox2, its role in the hereditary pathology of the nervous system and in brain tumors, with possible implications for therapy.
Results obtained and future plans:
Sox2 is essential for the development of the early embryo and the maintenance of embryonic stem cells, where it interacts, functionally or physically, with other pluripotency factors, such as nanog and Oct4 (1). In humans, Sox2 heterozygous mutation compromises the development of the brain, particularly the hippocampus and eye. Our work in mouse shows that conditional tissue-specific ablation of Sox2 in the brain causes the loss of important regions of the developing forebrain (ventral telencephalon) and severe damage of the hippocampus dentate gyrus; neural stem cells, in vitro and in vivo, require Sox2 for long-term self-renewal and maintenance (2,3). To identify molecular targets of Sox2, we identified Sox2 binding sites in chromatin, and compared normal and Sox2-deleted neural stem cells by determining their RNAs (RNAseq), characterizing the changes in long-range interactions between genes and regulatory regions, identifying a number of potential Sox2-dependent enhancers connected in a network of physical, and possibly functional, interactions (4, and in preparation). Among the regulated genes are genes important for brain development, some of which are involved in hereditary disease.
Sox2 is also required for other stem cell types, such as germ cells, neural crest cells etc. (5). Sox2 is expressed in cancer stem cells within neural tumors, and is required for their maintenance (6); these studies open the way to hypotheses for experimental therapies.
In the future, we will study functionally, among the genes regulated by Sox2, those that are more interesting for brain development and human disease, using technologies of mutagenesis in mouse, transgenic fishes, long-range chromatin interaction studies, assays of transcription factor binding in vivo (ChIA-PET, ChIPseq).
Silvia Nicolis graduated in Biology at the University of Milano, and obtained her PhD at the same University in 1992. Her initial work was on gene regulation in haematopoiesis. She then joined the National Institute of Medical Research in London as a postdoctoral fellow, where she generated mice carrying a null mutation in the Sox2 transcription factor gene by gene targeting, which demonstrated Sox2 requirement for the maintenance of the early embryonic stem cells of the epiblast. On her return to Italy, she worked at the University of Varese, then at the University of Milano-Bicocca (from 2000, Researcher; from 2004, Associate Professor in Genetics; 2013, abilitation to full professorship, Genetics), where she set up her laboratory working on the genetics of brain development and disease, by functional genetic approaches in mouse and neural stem cells, with a focus on the study of the Sox2 transcription factor.
1. Avilion A, Nicolis S, Pevny L, Perez L, Vivian N and Lovell-Badge R Multipotent cell lineages in early mouse development require Sox2 function. Genes and Development 17:126-140, 2003
2. Favaro R, Valotta M, Ferri A, Latorre E, Mariani J, Giachino C, Lancini C, Tosetti V, Ottolenghi S, Taylor V and Nicolis, SK Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh. Nature Neuroscience 12: 1248-1256, 2009
3. Ferri A, Favaro R, Beccari L, Bertolini J, Mercurio S, Nieto-Lopez F, Verzeroli C, La Regina F, De Pietri Tonelli D, Ottolenghi S, Bovolenta P and Nicolis SK. Sox2 is required for embryonic development of the ventral telencephalon through the activation of the ventral determinants Nkx2.1 and Shh. Development 140:1250-61, 2013
4. Zhang Y, Wong C-H, Birnbaum R, Li G, Favaro R, Ngan CY, Lim J, Tai E, Poh HM, Mulawadi, Nicolis S, Ahituv N, Ruan Y, Wong E, Wei CL. Chromatin connectivity maps reveal dynamic promoter-enhancer long-range associations. Nature 504:306-10, 2013
5. Campolo F, Gori M, Favaro R, Nicolis S, Pellegrini M, Botti F, Rossi P, Jannini EA, Dolci S. Essential role of sox2 for the establishment and maintenance of the germ cell line. Stem Cells 31:1408-21, 2013
6. Favaro R, Appolloni I, Pellegatta S, Badiola Sanga A, Pagella P, Gambini E, Pisati F, Ottolenghi S, Foti M, Finocchiaro G, Malatesta P and Nicolis SK. Sox2 is required to maintain cancer stem cells in a mouse model of high-grade oligodendroglioma. Cancer Res., 74:1833-44, 2014