The Ferretti Laboratory: Lineage choice and mesodermal competence
"Our aim is to understand how cell signaling pathways and transcription factor networks interact during early embryonic development
Gene expression is tightly regulated and requires communication between cellular signals and TFs, binding of the TFs to specificcis regulatory modules (CRMs) and recruitment of chromatin-modifying enzymes. Deciphering the regulatory language encoded by the genome is one of the most important objectives in modern biology. Transcriptional priming represents a powerful and still unexplored mechanism linking cell signaling and cell fate specification. Indeed, pioneer TFs may be the key for converting signaling pathways into a specific transcriptional program. Although they are transcriptionally silent, pioneer TFs regulate gene expression by opening the chromatin, allowing the recruitment of lineage specific TFs and enabling the acquisition of a specific cell fate. Our primary goal is to understand how pioneer factors promote cell identity within the primitive streak.
The Ferretti group has a special interest in understanding the priming activity of the Pbx family members. Pbx proteins (Pbx1, Pbx2, Pbx3) are global and obligated cofactors of homeodomain proteins, which play fundamental roles in vertebrate organogenesis. As demonstrated by Pbx loss-of-function studies in the mouse, Pbx genes have pleiotropic roles in the formation of multiple essential organs such as cranium, axial and appendicular skeleton, heart, spleen, pancreas, urogenital and gastrointestinal tract development.
Pbx proteins are initially expressed in the primitive streak, the region of the embryo that will produce all mesoderm progenitors, and are critical for promoting mesodermal specification. Experimentally, Ferretti’s projects focused on 1 Cell fate specification, 2 Organogenesis, 3 Cancer invasions (Epithelial to Mesenchymal Transition, EMT).
The research approach in Ferretti group is to employ mouse models and cell line cultures and research resources such biochemistry, flow cytometry, genetics and proteomics to establish how pioneer factors drive cell fate and organogenesis, and become perturbed during the initiation and progression of cancers.
Selected scientific publications
Golonzhka, Olga, Alex Nord, Paul L F. Tang, Susan Lindtner, Athena R Ypsilanti, Elisabetta Ferretti, Axel Visel, Licia Selleri & John L R. Rubenstein (2015). Pbx Regulates Patterning of the Cerebral Cortex in Progenitors and Postmitotic Neurons. Neuron, 88(6), 1192-1207, doi:10.1016/j.neuron.2015.10.045.
Handschuh, Karen, Jennifer Feenstra, Matthew Koss, Elisabetta Ferretti, Maurizio Risolino, Rediet Zewdu, Michelle A. Sahai, Jean-Denis Bénazet, Xiao P. Peng, Michael J. Depew, Laura Quintana, James Sharpe, Baolin Wang, Heather Alcorn, Roberta Rivi, Stephen Butcher, J. Robert Manak, Thomas Vaccari, Harel Weinstein, Kathryn V. Anderson, Elizabeth Lacy, Licia Selleri (2014). ESCRT-II/Vps25 constrains digit number by endosome-mediated selective modulation of FGF-SHH signaling. Cell Reports, 9(2), 674-87, doi: 10.1016/j.celrep.2014.09.019.
Feldhahn, Niklas, Elisabetta Ferretti, Davide Robbiani, Elsa Callen, Stephanie Deroubaix, Licia Selleri, Andre Nussenzweig & Michel C. Nussenzweig (2012). The hSSB1 orthologue Obfc2b is essential for skeletogenesis but dispensable for the DNA damage response in vivo. EMBO Journal, 31(20), 4045-4056, doi: 10.1038/emboj.2012.247.
Sgado, Paola, Elisabetta Ferretti, Daniel Grbec, Yuri Bozzi & Horst H. Simon (2012).The atypical homeoprotein Pbx1a participates in the axonal pathfinding of mesencephalic dopaminergic neurons. Neural Development, 7(24), doi:10.1186/1749-8104-7-24.
Ferretti, Elisabetta, Bingsi Li, Rediet Zewdu, Victoria Wells, Jean M. Hebert, Courtney Karner, Matthew J. Anderson, Trevor Williams, Jill Dixon, Michael J. Dixon, Michael J. Depew & Licia Selleri (2011). A Conserved Pbx-Wnt-p63-Irf6 Regulatory Module Controls Face Morphogenesis by Promoting Epithelial Apoptosis. Developmental Cell,21(4), 627-641, doi:10.1016/j.devcel.2011.08.005. (Highlight on the “Faculty of 1000” and “Science” magazine in their “Editor’s Choice” editorial (issue of 28 October 2011).
“By using mouse models, I identified the molecular network (Pbx-Wnt-p63-Irf6) that controls midface morphogenesis and I found that disruption within this molecular network leads to cleft lip and palate to (CL/P), which is the most common craniofacial birth defect. In a critical genetic rescue experiment, I was able to completely repair the CL/P in Pbx mutant embryos. These results have had a considerable importance for developing targeted treatments to cure human craniofacial congenital malformations in utero.”
Vitobello, Antonio*, Elisabetta Ferretti*, Xavier Lampe, Nathalie Vilain, Sebastien Ducret, Michela Ori, Jean-Francois Spetz, Licia Selleri & Filippo M. Rijli (2011). Hox and Pbx Factors Control Retinoic Acid Synthesis during Hindbrain Segmentation.Developmental Cell, 20(4), 469-482, doi: 10.1016/j.devcel.2011.03.011. *authors contributed equally.
“I used Pbx mouse mutants, which have defective hindbrain segmentation, as a model to study how the nervous system develops. I discovered a novel Pbx-dependent molecular mechanism governing mesodermal RA levels, which in turn controls proper hindbrain development. I found that in the embryonic mesoderm Pbx genes control RA levels by direct transcriptional regulation of the RA synthesizing enzyme. Ultimately, these results provided novel insights into the understanding of the congenital abnormalities of the nervous system.”