The major interest of my laboratory is the control of proliferation in normal and cancer cells and the genes and gene-products whose interplay regulates proliferation and differentiation.
To understand how growth factors mediate cell proliferation and differentiation, we are studying the mechanism of action and the regulation of expression of fibroblast growth factors (FGF). FGF represents a large family of growth factors which signal through their interaction with tyrosine kinase receptors (FGFR) which also make-up a gene family. FGF signaling plays a major role in a variety of developmental processes, ranging from gastrulation to bone morphogenesis. Ectopic or excessive FGF expression can lead to oncogenesis. The main projects currently being carried out include:
1) The regulation of expression of the FGF4 gene in vitro and in vivo. FGF4 is an important signaling molecule whose expression is physiologically restricted to embryonic life and plays an essential role in early embryonic development. We have found that its expression depends on distinct enhancer elements, all located in the 3? portion of the gene, that, by interacting with specific transcription factors, direct FGF4 expression in specific embryonic structures, including the blastocyst, myotomes and limb buds. The transcription factors which interact with the blastocyst enhancer have been identified. Sox2 and Oct-3 synergistically activate FGF expression in this tissue by binding to adjacent regions in the enhancer DNA.
2) The physiological role of FGFs, using transgenic mice or gene-ablation techniques. We have generated FGF1, FGF2 and FGF1/FGF2 knockout mice and show that these factors play no essential role in development, but affect the production of specific neurons, the development of hematopoietic precursor cells, and wound-healing. We are in the process of generating mice in which specific FGF4 DNA regulating elements have been deleted, to determine the role of this factor in distinct processes of development (e.g. limb formation).
3) The regulation of bone development by FGF signaling. Unregulated FGF signaling, due to FGFR activating mutations, causes a variety of dominant bone morphogenetic disorders in humans, including several forms of dwarfism and craniosynostosis syndromes, showing that FGF signaling plays an important role in bone development. We are studying the effect of FGF on the two major cell types involved in bone formation, chondrocytes and osteoblasts. A) In chondrocytes, we found that FGF signaling inhibits proliferation and increases apoptosis both in vitro and in vivo. These effects are cell type-specific and require the activation of STAT1, a signal transducing transcription factor which is not normally activated by FGF in other cell types. We are investigating the other downstream effectors of FGF-mediated growth inhibition, how FGFs influence chondrocyte differentiation and the genes whose expression is induced by FGF signaling in chondrocytes and is controlled by STAT1. B) In osteoblasts, FGF signaling has dual effects. Immature osteoblasts respond with stimulation of proliferation, while in differentiating osteoblasts FGFs induce apoptosis. The proapoptotic effect of FGF on osteoblasts can also be demonstrated in vivo in transgenic animals overexpressing FGF2. We are presently investigating the mechanisms by which FGF induces apoptosis in differentiating osteoblasts and the physiological role of this phenomenon in intramembranous ossification, i.e. the formation of the flat bones of the skull. By introducing mutations into the FGFR2 gene, in ES cells, we are also attempting to create mouse models of craniosynostosis, to better study in vivo the alterations of osteoblast proliferation and differentiation that lead to these syndromes.
Research Professor, Department of Microbiology
Professor Emeritus of Microbiology, Department of Microbiology
Fellowship, California Institute of Technology, Virology and Cell Culture
Residency, University of Milan
Stem cells. 2017 Sep 29; 35(12):2340-2350
Molecular & cellular proteomics. 2017 Mar 15; 16(6):1126-1137
Oncotarget. 2016 Sep 20; 7(38):60954-60970
Nature communications. 2015 Apr 02; 6:6411-6411
Nature methods. 2014 May; 11(5):559-565
The role of FGF/FGFR signaling in cranial integration: Implications for primate evolution [Meeting Abstract]
American journal of physical anthropology. 2014 Mar; 153 58 58(SI):240-240
Cancer letters. 2013 Sep 10; 338(1):158-167