Group Leader: Felice Tirone
Topic: Neurobiology, Molecular Oncology, Muscle biology
KEYWORDS: Adult neurogenesis, neurogenic stimuli, gene therapy

 

Since more than a decade Felice Tirone and his laboratory are studying the dynamics of adult neurogenesis in the two neurogenic brain niches that continue to generate new neurons during adulthood, i.e., the dentate gyrus of the hippocampus and the subventricular zone, as well asin the postnatal cerebellum, which shows a transient but strong process of neurogenesis after birth. The continued production of new neurons during adulthood in the hippocampus plays an important role in improving the efficiency of episodic and associative memory, as shown by several laboratories including our’s. For our studies on neurogenesis we have generated mouse models with genetic alterations in genes that regulate the processes of proliferation and differentiation of neural stem cells. Our efforts are thus aimed to elucidate at the cellular and genetic levels the processes of self-renewal and differentiation as well as the functional aspects (memory) of stem cells, neural progenitors and mature neurons in the hippocampus, the subventricular zone and the cerebellum.

We are focusing in particular on two projects. In first place, we are testing the ability of different neurogenic stimuli to reactivate neural stem cells characterized by defective proliferation and differentiation; we are experimentally evaluating the interplay between the genetic controls of cell cycle and differentiation, as regulators of the maturation of stem cell in adult neurons. In this way, we have found procedures to efficiently reactivate neural stem cells in vivo.

A second key project is focused on finding new therapies to counteract the growth of medulloblastoma, the cerebellum tumor which originates from progenitor cells of cerebellar granule neurons. We have identified two medulloblastoma suppressors, the gene Tis21 and the chemokine Cxcl3, which are presently under preclinical validation through studies performed at at different stages of tumor development.
We have also studied during the last years also the process of maturation of the stem cells of the skeletal muscle (satellite cells), identifying a gene (IFRD1) that stimulates their regeneration.

Key Pubblications

1) Farioli-Vecchioli S, Saraulli D, Costanzi M, Pacioni S, Cinà I, Aceti M, Micheli L, Bacci A, Cestari V, and Tirone F. (2008) The timing of differentiation of adult hippocampal neurons is crucial for spatial memory. PLoS Biol 6(10): e143.

2) Farioli-Vecchioli S, Micheli L, Saraulli D, Ceccarelli M, Cannas S, Scardigli R, Leonardi L, Cinà I, Costanzi M, Ciotti MT, Moreira P, Rouault JP, Cestari V, Tirone F. 2012. Btg1 is Required to Maintain the Pool of Stem and Progenitor Cells of the Dentate Gyrus and Subventricular Zone. Front Neurosci. 6:124. Epub 2012.

3) Farioli-Vecchioli S, Cinà I, Ceccarelli M, Micheli L, Leonardi L, Ciotti MT, De Bardi M, Di Rocco C, Pallini R, Cavallaro S, Tirone F. 2012. Tis21 knock-out enhances the frequency of medulloblastoma in patched1 heterozygous mice by inhibiting the Cxcl3-dependent migration of cerebellar neurons. J Neurosci. 32:15547-15564.

4) Micheli L, D’Andrea G, Ceccarelli M, Ferri A, Scardigli R, Tirone F. (2019). p16Ink4a Prevents the Activation of Aged Quiescent Dentate Gyrus Stem Cells by Physical Exercise. Front Cell Neurosci 13:10. doi: 10.3389/fncel.2019.00010.

5) D’Andrea G, Ceccarelli M, Bernini R, Clemente M, Santi L, Caruso C, Micheli L, Tirone F. (2020). Hydroxytyrosol stimulates neurogenesis in aged dentate gyrus by enhancing stem and progenitor cell proliferation and neuron survival. FASEB J. 34:4512-4526. doi: 10.1096/fj.201902643R.

Research Group

 

Researchers :
Laura Micheli 

Post-doctoral fellows :
Manuela Ceccarelli 
email: manu.ceccarelli@gmail.com

PhD student:
Giorgio D’Andrea

 

Programs & resoucers

  • Scientific responsible of the Project funded by Fondazione Giovanni Celeghin. Title: Preclinical validation of a novel medulloblastoma therapy employing the chemokine Cxcl3. 2020-2022.
  • Scientific coordinator of Project of Lazio Innova (Regione Lazio), Title: Recurrent medulloblastoma: molecular studies in new preclinical models, for new therapies in humans. Number 85-2017-14785-L.R. 13/2008 CUP B56C17000140002 – from 01/6/2018 to 30/12/2020.
  • Scientific unit participating to the Project of the Ministry of Treasure and Finance, FaReBio di Qualità – Drugs and Biotechnological Networks of Quality – 30/6/2011- 30/06/2015.
  • Scientific unit of the Project in the framework agreement between CNR and Foundation EBRI. Title of FTirone Project: “The role of neurogenesis in memory processes.” 2010-in progress.
  • Scientific responsible of the project funded by the Italian Association for Cancer Research (AIRC) n°9251, years 2009-2012: “Targeting the medulloblastoma inhibitory gene PC3/BTG2 to neoplastic cerebellar progenitors cells and neurons.”
  • Scientific responsible of the Project of Research of National Interest (PRIN) 20074Z3H3N_003 funded by MIUR (Ministry of University and Research). Title: Transcriptional regulation of the proliferative and differentiative mechanisms in the neuron and their implication in tumorigenesis. Years 2009-2011.
  • Scientific responsible of the Project funded by FILAS (Finanziaria Laziale per lo sviluppo) Regione Lazio. Title: Development and validation of gene-profiling systems for diagnosis and prognosis of medulloblastoma and glioma, tumors of the central nervous system. Years 2009-2012.
  • Coordinator of the international Italy-Israel FIRB project (Investment Fund of Basic Research from Ministry of University and Research): “Gene control of the development of cerebellum and during medulloblastoma tumorigenesis”. 2006-2009: Project RBIN04P4ET.
  • Scientific responsible of the Telethon project: GGP05082, 2005-2008: Role of the gene PC4/IFRD1 in muscle and neuron regeneration.
  • Scientific responsible of the project funded by Compagnia di San Paolo, years 2004-2008: Study of the proneural and antiproliferative gene PC3 in the development of cerebellum and in the onset of the cerebellar tumor, medulloblastoma, and of its use in antitumor gene therapy.
  • Scientific responsible of the Research Unit of the Coordinated Project: “Dynamic analysis of the differentiative ways activated by different growth factors in stem cells”. Ministery of the University and Research-FIRB, 2003-2006: Project RBAU01PCRL
  • Scientific responsible for Italy of the European Community project FP5 (Grant: QLG3-CT-2000-00072), line of action 9.3 Brain development, disorders and repair. Title: “Genes controlling neuronal specification and differentiation”. 2000-2004.
  • Scientific responsible of the Operative Research Unit of the Strategic Project Oncology CNR-MIUR, 2000-2001 and 2002-2004 (BRIDGE): Regulation of cyclin D1 by the antiproliferative gene PC3, inducible by p53, during DNA damage and tumorigenesis.
  • Alpha Recipient of private donation provided by Mrs. Maria Bianchi, years 1997-2008. Project title: Study of genes regulated by NGF.
  • Scientific responsible of the Telethon project: A046, 1995-1998: Studies on the molecular and biological function of the muscle differentiation regulatory protein PC4.
  • Scientific responsible of the Telethon project: A108, 1991-1994: Molecular studies in the muscle of a nerve growth factor inducible gene, PC4, which is expressed in myoblasts and regulated during their differentiation to myotubes.
  • Scientific responsible of the project of the Italian Association for Cancer Research, 1994: Study of the nerve growth factor-regulated gene as a potential anti-oncogene.
  • Scientific responsible of the Istituto Superiore di Sanità project, 1991-1992: Study of the effects of nerve growth factor and of NGF-regulated genes on viral replication.
  • Unit head of the CNR project “Finalizzato” Genetic Engineering 1990-1995: Study of gene regulated by nerve growth factor and expressed during embryonic differentiation