CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Signalling, chromatin remodelling and Gene Expression

One of the key questions in cell biology is how effectors link extracellular stimuli to cellular responses in terms of gene expression and chromatin remodelling. My laboratory is interested in understanding the functions and regulation of proteins able to read the genetic and epigenetic chromatin signals and than control the gene expression.

Signaling-MAPK p42/p44

 

The Ras-Raf-MEK-ERK pathway provides a signal transduction link between cell surface receptors and the nucleus and it has been implicated in several processes such as proliferation, differentiation, motility and synaptic plasticity. The Extracellular Regulated Kinase 1 and 2 ERK1/2 (also known as Mitogen Associated Kinase MAPK p42/p44) are the final effectors of this pathway originated by external stimuli at the cell membrane and mediated by Ras GTPases. Once activated in the cytoplasm, ERK1 and ERK2 translocate into the nucleus and interact with nuclear substrates to induce specific programs of gene expression. The interest of the lab is understand the structural determinants and functional differences between ERK1 and 2. We use molecular and biochemical techniques as well as in-vivo imaging to monitor nucleo-cytoplasmic trafficking of fluorescently tagged ERK1 and ERK2. Recently we demonstrated that ERK1 shuttles across the nuclear membrane at a much slower rate than ERK2 and at the present we are looking for critical aminoacid and domains involved the nuclear permeation of this kinase.

Rett syndrome and chromatin remodelling

Rett Syndrome (RTT) is an X−linked genetic disease with an incidence of 1/10000 born children without any effective pharmacological treatment. Mutations in the coding sequence of the Methyl CpG–binding protein 2 (MeCP2) gene are present in around 80% of the patients diagnosed with the classic form of Rett syndrome. A proportion of atypical cases results from mutations in cyclin-dependent kinase-like 5 (CDKL5) or in the Forkheads-Box gene (FOXG1) sequence. At the molecular level, it is well established that MeCP2 and FOXG1 act as transcriptional repressors, with both direct and indirect mechanisms, through DNA-binding. We are interested in the study of the spatio-temporal localization of MeCP2, CDKL5 and FOXG1 and relative pathological mutants tagged with fluorescent proteins in different cellular models including primary neurons and glial cells obtained from the mouse cortex.

 

MeCP2 is a nuclear protein abundant in pericentric heterochromatin and its localisation reflects the distribution of methylated dinucleotides. The human MeCP2 is characterised by two important domains: the Methyl CpG-Binding Domain (MBD), permitting the binding to methylated CpGs and a Transcriptional Repression Domain (TRD) interacting with the Sin3A-histone deacetylase complex. Furthermore, it is also believed that MeCP2 is able to repress transcription by mechanisms independent of histone acetylation, including the reorganisation of secondary chromatin structures.

 

Publications

  • Maffei M, Funicello M, Vottari T, Gamucci O, Costa M, Lisi S, Viegi A, Ciampi O, Bardi G, Vitti P, Pinchera A, Santini F (2009) The obesity and inflammatory marker haptoglobin attracts monocytes via interaction with chemokine (C-C motif) receptor 2 (CCR2). BMC Biol. 7:87.
  • Bardi G, Vittorio O, Maffei M, Pizzorusso T, Costa M (2009) Adipocytes differentiation in the presence of Pluronic F127-coated carbon nanotubes. Nanomedicine 5:378-81.
  • Marchi M, D'Antoni A, Formentini I, Parra R, Brambilla R, Ratto GM, Costa M (2008) The N-terminal domain of ERK1 accounts for the functional differences with ERK2. PLoS ONE 3:e3873.
  • Bardi G, Tognini P, Ciofani G, Raffa V, Costa M, Pizzorusso T (2009) Pluronic-coated carbon nanotubes do not induce degeneration of cortical neurons in vivo and in vitro. 5:96-104.
  • Marchi M, Guarda A, Bergo A, Landsberger N, Kilstrup-Nielsen C, Ratto GM, Costa M (2007) Spatio-temporal dynamics and localization of MeCP2 and pathological mutants in living cells. Epigenetics 2:187-97.
  • Putignano E, Lonetti G, Cancedda L, Ratto G, Costa M, Maffei L, Pizzorusso T (2007) Developmental downregulation of histone posttranslational modifications regulates visual cortical plasticity. Neuron 53:747-59.
  • Costa M, Marchi M, Cardarelli F, Roy A, Beltram F, Maffei L, Ratto GM (2006) Dynamic regulation of ERK2 nuclear translocation and mobility in living cells. J. Cell. Sci. 119:4952-63.
  • Costa M, Barogi S, Socci ND, Angeloni D, Maffei M, Baragatti B, Chiellini C, Grasso E, Coceani F (2006) Gene expression in ductus arteriosus and aorta: comparison of birth and oxygen effects. Physiol. Genomics 25:250-62.

Grants

2008 to 2010: EURORET, partner

2009 to 2011: PRIN, Italian Ministry of University and Scientific Research

Collaborations

  • A. Cuschieri, Institute of Medical Science and Technology, University of Dundee, UK.
  • A. Cattaneo, Scuola Normale Superiore, Pisa, Italy.
  • C. Basilico, New York Medical Center, New York, USA.

 

no PI photo

Mario Costa

Contact information

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Participating staff
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