Graziella Messina
Graziella Messina
affiliation: Università di Milano
research area(s): Developmental Biology, Stem Cells And Regenerative Medicine
Course: Biomolecular Sciences
University/Istitution: Università di Milano
March 2004 Ph.D. in Cellular and Developmental Biology, "Sapienza" University of Rome- Italy
December 1999 Undergraduate Biology Degree with honors (110/110 cum laude), "Sapienza" University of Rome- Italy
Professional Experience
December 2008- present: Assistant Professor ("Ricercatore a tempo determinato", SSD BIO/17) and Principal Investigator at the Department of Biology,
University of Milan, Italy.
January 2008 Young Researcher fellowship (3 years) from the FIRB (Fondo per gli investimenti della ricerca di base) for researching on "Stem cells in
cardiovascular diseases: from biology to clinical application" at the San Raffaele Scientific Institute, Milan, Italy. Supervisor: Prof. Giulio Cossu.
2006-2007 Fellowship from the MDA (Muscular Distrophy Association) Grant for researching on "Pericytes of human post-natal skeletal muscle for the cell
therapy of muscular dystrophy" , at the San Raffaele Scientific Institute, Milan, Italy. Supervisor: Dr. Giulio Cossu.
2004-2006 Post-doctoral Grant (Assegno di Ricerca) from "Sapienza" University of Rome- Italy
for researching on "Regulation of Myogenic Differentiation in vitro and transforming mechanisms by oncogenic retroviruses", at the San Raffaele Scientific Institute,
Milan, Italy. Supervisor: Prof. Giulio Cossu.
Teaching activity - Course Instruction
2008-present: Cytology/Histology and Developmental Biology courses in the undergraduate course of Biology at the University of Milan (Italy)
2000-2008: Lectures in the course of Virology at the University of Rome (Italy)
Teaching activity - Trainee supervision
- Martina Ragazzi: undergraduate student in Biology, Univ. Milan (2009-present).
- Sara Benedetti: (PhD student), Univ. Rome (supervisor Prof. G.Cossu). (2008-present)
- Sara Benedetti: undergraduate student in Biology, Univ. Milan (supervisor Prof. G.Cossu) (2005-2007)
- Eleonora Lapi: undergraduate student in Biology, Univ. Milan (supervisor Dr. M. Grossi) (2000-2002)
Peer Review
Manuscript reviewer for: Cell Death and Differentiation, Cell Death and Disease
Funding ID
Pending grant:
- 2010: Italian Ministry of Health - Bando Giovani Ricercatori. "Role of the transcription factor Nfix in muscle development in vertebrates" - 3-years project,
100.000 " / year. Applicant's role: PI
Running grant
- 2009-2011: three-year start-up grant PUR 2009 from the Italian Ministry of Research- 4.500 ". Applicant's role: PI. ID:12/01/006/62
My scientific activity has been focused on the study and characterization of the mechanisms that regulate skeletal muscle development. Using both myogenic and multipotent mesoderm progenitor cells (mesoangioblasts) as models, I studied the role of the cell cycle regulators, signal transduction molecules and transcription factors in specification and differentiation of skeletal muscle.
My major findings can be summarized as follows:
- demonstration of the role of cell-cell contact, N-Cadherin-mediated (community effect) and of the cell cycle inhibitor p27Kip1 in myogenic terminal differentiation;
- the elucidation of the role of small GTPase of the Rho family in the regulation of terminal differentiation;
- identification of Nfix as a key factor regulating the transcriptional switch from embryonic to fetal myogenesis;
- characterization of regulatory molecules (Pax3 and Pw1) that commit multipotent adult progenitor cells (mesoangioblasts) to skeletal myogenesis.
ii. Recognition and diffusion of applicant"s early contributions.
I earned my PhD degree (2004) in Cellular and Developmental Biology with a project conducted in the laboratory of the late Prof. Franco Tatò ("Sapienza" University of Rome, Italy). I focused on the mechanisms controlling normal myogenesis, and in particular, the molecules controlling cell cycle exit, a requirement for myogenic differentiation, in order to better understand how these oncogenic retroviruses act. My studies demonstrated the existence of a tight cross-talk between cell cycle and myogenic regulators, leading to two first authorship publications in good impact journals in the field of cell biology (Messina et al., MBC 2005; Travaglione*, Messina* et al., Cell Death Diff, 2005; * co-first authors).
In order to combine my background in cell biology with a solid foundation in developmental biology, for my postdoctoral training (2004-2007), I joined the laboratory of Prof. Giulio Cossu, at the San Raffaele Scientific Institute (Milan-Italy). In the Cossu lab, I began to study the molecules responsible for myoblast diversification (Biressi*, Messina* et al., Cell Death Diff, 2007; * co-first authors) during mouse development (embryonic and fetal myoblasts). This work led to the identification of the transcription factor Nfix as a master molecular switch that specifically repress expression of embryonic genes and activates fetal genes in developing muscle. This study led to first authorship publication on Cell (Messina et al., Cell, 2010). For this work, I was awarded the Honorary Mention for the best work from the Society for Muscle Biology- Frontiers in Myogenesis " Callaway Garden, Georgia, USA (2006). During these years, I also studied a class of vessel associated progenitor cells, termed "mesoangioblasts", isolated and characterized in Cossu laboratory. When transplanted in vivo, mesoangioblasts give rise to multiple differentiated mesodermal phenotypes such as smooth and skeletal muscle, cartilage and bone. When wild type or dystrophic, genetically corrected, mesoangioblasts were delivered intra-arterially to dystrophic muscle of α-sarcoglycan null mice (a model for Limb Girdle muscular dystrophy), they resulted in a dramatic functional amelioration of the dystrophic phenotype. Within this topic, I focused on the identification of molecules potentially responsible for myogenic commitment of mesoangioblasts. I carried out this work by studying Pax3 in collaboration with Margaret Buckingham, working for some months (2006 and 2007) in her lab at the Pasteur Institute (Paris). This work resulted in a first author publication (Messina et al., Stem Cells, 2008). Subsequently, I studied a Pax3 target, Pw1 in collaboration with David Sassoon, performing experiments in his lab at INSERM- Groupe Myologie at Hopital Salpetierre (Paris). The results have led to a manuscript now submitted (Bonfanti et al.) where I am senior and corresponding author. During my post-doc, I also coauthored together with my Post-doc supervisor one book chapter, two reviews in important journals (Messina and Cossu, Genes and Dev, 2009; Tedesco et al., JCI, 2010) and I presented several communications at international meetings (see CV section). I also supervised undergraduate student and PhD students. In addition, I was involved in collaborative studies with different research groups.
During years 2000-2008, I also had a constant teaching activity initially in Virology at the University of Rome (Italy), and later in Cytology and Histology at the University of Milan (Italy). In December 2008, I obtained, through a national competition, a tenure-track Assistant Professor position at the University of Milan. Here I am Principal Investigator of the Laboratory at the Department of Biology and I am Professor of Developmental Biology courses in the undergraduate course of Biology.
1. Messina G., Blasi C., La Rocca SA, Pompili M., Calconi A. and M. Grossi. p27Kip1 Acts Downstream of N-Cadherin-mediated Cell Adhesion to Promote Myogenesis beyond Cell CycleRegulation. MBC, 2005 March, vol 16, 1469-1480

2. Travaglione S1., Messina G1., Fabbri A., Falzano L., Giammarioli A.M., Grossi M., Rufini S. and Fiorentini C. "Cytotoxic necrotizing factor 1 hinders skeletal muscle differentiation in vitro by perturbing the activation/deactivation balance of Rho GTPases". 1 equally contributed; Cell Death Diff, 2005 Jan, 12 (1): 78-86

3. Dellavalle, M. Sampaolesi, R.Tonlorenzi, E. Tagliafico, B. Sacchetti, L. Perani, Innocenzi A., B. G. Galvez, G. Messina, R.Morosetti, S. Li, G. Peretti, J. S. Chamberlain, W. E. Wright,Y. Torrente, S. Ferrari, P. Bianco, and G. Cossu. "Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells". Nat Cell Biol. 2007 Mar;9(3):255-67

4. L. Castaldi, C. Serra, F. Moretti, G. Messina, R. Paoletti, M. Sampaolesi, Torgovnick, M. Baiocchi, F. Padula, A. Pisaniello, M. Molinaro, G. Cossu, M. Levrero and M. Bouché. "Bisperoxiovanadium, a phospho-tyrosine phosphatase inhibitor, reprograms myogenic cells to acquire a pluripotent, circulating phenothype". Faseb J, 2007 July 17

5. Biressi S.1, Messina G.1, Tagliafico E., Collombat P., Monteverde S., Broccoli V., Mansouri A., Cusella-De Angelis M.G., Tajbakhsh S., Ferrari S. and G. Cossu.
"The homeobox-gene ARX is a positive regulator of embryonic myogenesis" Cell Death Diff. 2007 Oct 12 1equally contributed

6. Messina G., Biressi S. and G. Cossu "Non muscle stem cells and muscle regeneration". Chapter of "Skeletal Muscle Repair and Regeneration". Springer Netherlands book, Sep2007, chapter 4: 65-85

7. Messina G., Sirabella D., Monteverde S., Galvez G.B., Tonlorenzi R., Schnapp E., DeAngelis L., Brunelli S., Relaix F., Buckingham M. and G. Cossu . "Skeletal Muscle Differentiation Of Embryonic Mesoangioblasts Requires Pax3 Activity" Stem Cells, 2008 Oct 9

8. Hoshiya H, Kazuki Y, Abe S, Takiguchi M, Kajitani N, Watanabe Y, Yoshino T, Shirayoshi Y, Higaki K, Messina G, Cossu G, Oshimura M. "A highly Stable and Nonintegrated Human Artificial Chromosome (HAC) Containing the 2.4 Mb Entire Human Dystrophin Gene". Mol Ther. 2008 Nov 25

9. Messina G and G Cossu. The origin of embryonic and fetal myoblasts: a role of Pax3 and Pax7. 2009 GENES & DEVELOPMENT 23:902"905

10. Lagha M, Brunelli S, Messina G, Cumano A, Kume T, Relaix F and Buckingham ME. Pax3:Foxc2 Reciprocal Repression in the Somite Modulates Muscular versus Vascular Cell Fate Choice in Multipotent Progenitors. 2009 Dev Cell, 17, 892"899

11. Tedesco FS, Dellavalle A, Diaz-Manera J, Messina G and Cossu G. Repairing skeletal muscle: regenerative potential of skeletal muscle stem cells. 2010. J Clin Invest. 120, 11-19

12. Messina, G, Biressi, S, Monteverde S, Magli A, Cassano M, Perani L, Roncaglia E, Tagliafico E, Starnes L, Cambpell CE, Grossi M, Goldhamer DJ, Gronostajski RM, Cossu G. 2010 Nfix regulates fetal specific transcription in developing skeletal muscle. Cell 140, 554-566

13. J Dı´az-Manera, T Touvier, A Dellavalle, R Tonlorenzi, FS Tedesco, G Messina, M Meregalli, C Navarro, L Perani, C Bonfanti, I Illa, Y Torrente and G Cossu . Partial dysferlin reconstitution by adult murine mesoangioblasts is sufficient for full functional recovery in a murine model of dysferlinopathy. Cell Death and Disease (2010) 1, e61; doi:10.1038/cddis.2010.35

14. Magli A, Angelelli C, Ganassi M, Baruffaldi F, Matafora V, Battini R, Bachi A, Messina G, Rustighi A, Del Sal G, Ferrari S, Molinari S. Proline isomerase PIN1 represses terminal differentiation and myocyte enhancer factor 2C function in skeletal muscle cells. J Biol Chem. 2010 Nov 5; 285(45):34518-27.

15. Innocenzi A, Latella L, Messina G, Simonatto M, Marullo F, Berghella L, Poizat C, Shu CW, Wang JY, Puri PL, Cossu G. An evolutionarily acquired genotoxic response discriminates MyoD from Myf5, and differentially regulates hypaxial and epaxial myogenesis. EMBO Rep. 2011 Jan 7.
16. S. Crippa, M. Cassano, G. Messina, D. Galli, B. G. Galvez, T. Curk, C. Altomare, F. Ronzoni, J. Toelen, R. Gijsbers, Z. Debyser, S. Janssens, B. Zupan, A. Zaza, G. Cossu, and M. Sampaolesi. miR669a and miR669q prevent skeletal muscle differentiation in postnatal cardiac progenitors. J Cell Biol 2011 Vol. 193 No. 7 1197"1212
Project Title:
Role of the transcription factor Nfix in muscle regeneration and muscular dystrophies
I will study the role of the transcription factor Nuclear Factor IX, Nfix, in post-natal skeletal muscle growth and regeneration, and in the pathogenesis of muscular dystrophies. I have recently demonstrated the role of the transcription factor Nuclear Factor IX, Nfix, in driving the transcriptional switch from embryonic to fetal myogenesis, characterized by a switch from slow to fast twitching and more mature fibres [1]. Preliminary data show that Nfix is also strongly expressed in satellite cells (SCs), the muscle adult stem cells responsible for post-natal muscle growth and regeneration. Therefore, I will investigate:
Aim 1. The role of Nfix in satellite cells (SCs) determination, quiescence and activation by studying these processes in two different models of Nfix null mouse. The ability of Nfix deficient SCs to repair muscle damage in comparison with wt SCs will be also evaluated.
Aim 2. The gene expression profile of the muscle-specific Nfix null SCs in vitro in comparison with wt SCs, in order to identify possible Nfix target genes in adult muscle and possible mechanisms through which Nfix could be also crucial in post-natal muscle growth and regeneration.
Aim 3. The possible effect of Nfix mis-expression in muscular dystrophies. Muscular dystrophies are characterized by primary wasting of skeletal muscle and currently lack a therapy. Among the different approaches, many efforts are directed to induce hypertrophy in dystrophic muscle to counteract progressive degeneration. This is achieved by enhancing regeneration at the expense of the satellite cell pool. Interestingly, fast muscle fibres are preferentially affected in different muscular dystrophies. As Nfix regulates slow myosin expression, I propose that a slower twitching muscle may escape muscle degeneration in a dystrophic mouse model. In this perspective, the possible interference of Nfix with the pathogenesis of muscular dystrophy will be studied by crossing muscle-specific Nfix null mice with α-sarcolgycan null mice (which is a model for Limb Girdle 2D muscular dystrophy).
The results of this study will have important implications for the understanding of the mechanisms regulating post-natal muscle growth and regeneration and potentially lead to a novel therapy for muscular dystrophy.