Source: Interfolio F180
Giordano Lippi
Research Focus
Neurons have unique gene expression challenges in space and time. The polarized morphology that is essential for their function emerges from strict compartmentalization of gene products. Because of the distance between the nucleus and the dendrites and axon, neurons regulate protein production locally, so that the rapid changes required for plasticity can occur. In addition, neurons undergo profound changes in gene expression during development, allowing them to acquire a variety of morphological features and find the appropriate synaptic partners. However, the molecular mechanisms that confer neurons these features remain largely unknown. The overarching goal of my research program is to address this gap using cutting edge technologies that we develop in the lab.
In particular, we focus on microRNAs (miRNAs), a family of non-coding RNAs, that are negative 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 non-coding RNA repertoire and miRNAs in particular. Many miRNAs 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 miRNA levels are linked to multiple neurodevelopmental disorders, including autism, schizophrenia and epilepsy.
We showed that miRNAs are master regulators of critical developmental windows in multiple neuronal subtypes (Lippi et al. 2016; Dulcis, Lippi et al. 2017; Taylor et al. 2023; Zolboot et al. 2023). For example, 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 miRNAs can trigger profound long-term consequences for network stability and function (Lippi et al. 2016, Taylor et al. 2023). The changes include excessive synaptic activity, propensity for seizure-like activity, and memory impairments, recurrent pathological features shared by many neurodevelopmental disorders. Using in vivo dissection of miRNA function, we identified and parsed out the molecular pathways regulated by the miRNAs to achieve a properly balanced network. Interestingly, several of the miRNA targets identified had already been linked to specific features of neurodevelopmental disorders. Taken together, these findings suggest that miRNAs tightly regulate a core of highly interconnected developmental programs that control critical developmental windows.
A major effort in the lab was devoted to re-engineer the toolbox to study gene expression and miRNAs in the brain (Zolboot et al. 2023). This includes: i) a peptide for fast (hours) and reversible global miRNA loss-of-function, allowing us to identify miRNA roles with unprecedented temporal resolution; ii) a mouse line for mapping miRNA-target interactions in rare neuronal subtypes, the necessary first step to understand how miRNAs instruct neuronal diversification; iii) tools to measure changes in translation at single-cell resolution; iv) RNA CRISPR systems to manipulate specific miRNA-target interactions. These tools allow us to ask much more sophisticated questions. Which miRNAs are enriched in different cell-types and what is the specific set of targets they regulate? What are the nodes where regulation of multiple miRNAs converges and why is redundant regulation necessary? What is the effect of selective removal of miRNAs from certain cell-types? Are miRNAs important for the development and function of these cell-types? What are the consequences for network activity and emerging cognitive functions? We are also very interested in evolutionary questions. What is the function of primate/human specific miRNAs? Are miRNAs responsible for the increase in neuronal cell types and cognitive abilities? The field has many fundamental questions that remain unresolved, and my lab is perfectly positioned to address many of them.
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.2009-2010 Career Development Fellow, MRC Toxicology Unit, Leicester, UK. Laboratory of Pierluigi Nicotera, Ph.D.
2004-2009 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
2018 Whitehall Foundation Award
Selected Publications
Taylor, S. R.; Kobayashi, M.; Vilella, A.; Tiwari, D.; Zolboot, N.; Du, J. X.; Spencer, K. R.; Hartzell, A.; Girgiss, C.; Abaci, Y. T.; Shao, Y.; De Sanctis, C.; Bellenchi, G. C.; Darnell, R. B.; Gross, C.; Zoli, M.; Berg, D. K.; Lippi, G. MicroRNA-218 instructs proper assembly of hippocampal networks. eLife 2023, 12.
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Zolboot, N.; Xiao, Y.; Du, J. X.; Ghanem, M. M.; Choi, S. Y.; Junn, M. J.; Zampa, F.; Huang, Z.; MacRae, I. J.; Lippi, G. MicroRNAs are necessary for the emergence of Purkinje cell identity. bioRxiv : the preprint server for biology 2023.
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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.
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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.
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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.
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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.
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