Source: Interfolio F180
Giordano Lippi
Research Focus
We work at the interface between hard-core molecular biology and circuits neuroscience. The goal is to identify the gene programs that build stable neural networks and that allow specific cell types to operate properly within the circuit. The Lippi lab is located at the Dorris Neuroscience Center (DNC), part of The Scripps Research Institute (TSRI), La Jolla, California. We are also associated with the Neurograd program at UCSD.
During their life-span neurons undergo profound changes in gene expression that trigger rapid transitions in their developmental trajectory. The overarching goal of the research in my lab is to identify the key molecular players that drive and coordinate these transcriptional changes. In particular, we focus on non-coding RNAs (ncRNAs), a novel and exciting class of master regulators of gene expression. Intriguingly, recent discoveries suggest that the number of protein-coding genes has changed very little from unicellular to complex multicellular organisms. Instead, the increase in biological complexity derives from additional layers of regulation of gene expression provided by the expansion of the ncRNA repertoire. Many ncRNAs are enriched in the brain and increase their expression during development, suggesting that they play fundamental roles in establishing properly balanced neural networks. Consistently, recent literature indicates that changes in ncRNA levels are linked to multiple neurodevelopmental disorders, including autism, schizophrenia and epilepsy. However, how ncRNAs instruct proper neural networks development is not known.
We were the first to show that microRNAs (miRs), a class of ncRNAs, are master regulators of a critical developmental window, during which most synaptic connections are formed. Using an array of techniques, including single unit recording in freely moving animals, calcium imaging, electrophysiology, and behavioral studies, we demonstrated that even a temporary inhibition of specific miRs can trigger profound long-term consequences for network stability and function (Lippi et al. 2016). The changes include excessive synaptic activity, propensity for seizure-like activity, and memory impairments, recurrent pathological features shared by many neurodevelopmental disorders. Using a set of molecular tools for in vivo dissection of miRs function, we identified and parsed out the molecular pathways regulated by the miRs to achieve a properly balanced network. Interestingly, several of the miR targets identified had already been linked to specific features of neurodevelopmental disorders. Taken together, these findings suggest that miRs tightly regulate a core of highly interconnected developmental programs that control critical developmental windows. They also suggest that ncRNAs can be used as tools to understand the transcriptional organisation that instructs proper neural network formation and how this process can go wrong at the onset of diseases.
We have now developed a set of genetics tools that will allow us to ask much more sophisticated questions. Which miRs are enriched in different cell-types and what is the specific set of targets they regulate? What are the nodes where regulation of multiple miRs converge and why is redundant regulation necessary? What is the effect of selective removal of miRs from certain cell-types? Are miRs important for the development and function of these cell-types? What are the consequences for network activity and emerging cognitive functions? What is the function of other less known ncRNAs (circular RNAs, long non coding RNAS, piwi RNAs, etc.)? We are also very interested in a second set of questions that will be carried out in iPSC cells. What is the function of primate/human specific miRs? Are these miRs responsible for the increase in primates' cognitive abilities? Addressing these questions requires techniques that span from genetics, cellular/molecular neuroscience, to imaging of large ensembles of neurons in vivo, and behaviour.
Education
Ph.D. (Biotechnology and Molecular Medicine), University of Modena and Reggio Emilia, 2009B.S. (Medical Biotechnology), University of Modena and Reggio Emilia, 2003
Professional Experience
2010-2017 Postdoctoral Research Fellow, Section of Neurobiology, University of California, San Diego, USA. Laboratory of Darwin K. Berg, Ph.D.2006-2010 Career Development Fellow, MRC Toxicology Unit, Leicester, UK. Laboratory of Pierluigi Nicotera, Ph.D.
2004-2010 Graduate Student, University of Modena and Reggio Emilia, Modena, Italy. Laboratory of Michele Zoli, Ph.D.
Awards & Professional Activities
2001 EU spinner Fellowship, University of Modena and Reggio Emilia2002 Italy-Belgium Travel Fellowship, University of Modena and Reggio Emilia
2005 EMBO short-term Fellowship, MRC Toxicology Unit
2006 MRC Career Development Fellowship, MRC Toxicology Unit
2016 CURE Taking flight award
2018 Whitehall Foundation Award
Selected Publications
Dulcis, D.; Lippi, G.; Stark, C. J.; Do, L. H.; Berg, D. K.; Spitzer, N. C. Neurotransmitter switching regulated by miRNAs controls changes in social preference. Neuron 2017, 95, 1319-1333.
[View]
Lippi, G.; Fernandes, C. C.; Ewell, L. A.; John, D.; Romoli, B.; Curia, G.; Taylor, S. R.; Frady, E. P.; Jensen, A. B.; Liu, J. C.; Chaabane, M. M.; Belal, C.; Nathanson, J. L.; Zoli, M.; Leutgeb, J. K.; Biagini, G.; Yeo, G. W.; Berg, D. K. MicroRNA-101 regulates multiple developmental programs to constrain excitation in adult neural networks. Neuron 2016, 92, 1337-1351.
[View]
Lippi, G.; Steinert, J. R.; Marczylo, E. L.; D'Oro, S.; Fiore, R.; Forsythe, I. D.; Schratt, G.; Zoli, M.; Nicotera, P.; Young, K. W. Targeting of the Arpc3 actin nucleation factor by miR-29a/b regulates dendritic spine morphology. Journal of Cell Biology 2011, 194, 889-904.
[View]
Ziviani, E.; Lippi, G.; Bano, D.; Munarriz, E.; Guiducci, S.; Zoli, M.; Young, K. W.; Nicotera, P. Ryanodine receptor-2 upregulation and nicotine-mediated plasticity. EMBO Journal 2011, 30, 194-204.
[View]