Venue: Centre Broca
Nicolas Panayotis
Group Leader Molecular Biology of Neuronal Transport Lab
Saints-Pères Paris Institute for the Neurosciences (SPPIN), CNRS UMR 8003
Université Paris Cité
Invited by Etienne Herzog (IINS)
Title
Deciphering the role of Importins Nuclear Transport Factors in CNS Functions and Neurodevelopmental Disorders
Abstract
Importins have key roles in the subcellular transport of proteins from the cytoplasm and synapse to the nucleus. While huge efforts helped to define the basic properties of nuclear the transport machinery, including the importin nuclear transport carriers, little attention has been paid to the roles of importins neuronal functions in vivo. Strikingly, if there was no clear evidence for the contributions of importins to specific neuronal functions and behaviors, several works pointed out to the involvement of importins in axonal regeneration of peripheral nerves and synaptic plasticity in neuronal cell cultures. Over the years, I explored the role of the importin family of nuclear import factors in vivo in a series of importin α single knockout mice. Together with evidence from behavioral, RNA-seq, slice recording, AAV-mediated gene dosage modulation, advanced imaging, biochemical, and pharmacological analyses, my work helped to discover the influence of importin α5 in anxiety pathways by regulating MeCP2 nuclear import in hippocampal neurons and the role of importin α3 in the nuclear shuttling of c-Fos in peripheral sensory neurons during chronic pain, and of importin β1 in memory. In addition, I used CMap, an in silico screening approach to identify candidate compounds mimicking the importin α5KO hippocampal transcriptional activity. Doing so, I identified β-sitosterol as a new anxiomimetic drug lead and validated its anxiolytic properties and synergy with fluoxetine in mice. My main goal is to decipher the roles of importin-dependent mechanisms, manipulate them to tackle MeCP2-related neurodevelopmental disorders, and optimize molecular treatments of these conditions. Parallel projects will follow up on the molecular interrogation of intriguing neuropsychiatric phenotypes identified in importin mutants.
Biosketch
Nicolas Panayotis is a Molecular Neurobiologist. He studied Neurobiology and Behavior at the Aix-Marseille University and obtained a Ph.D. in Medical Genetics at the Marseille Medical Genetics center (Inserm-MMG), under the direction of Dr. Jean-Christophe Roux. There he investigated the MeCP2-deficient mouse model for Rett Syndrome, a devastating genetic neurodevelopmental disorder.
He joined the group of Prof. Mike Fainzilber at the Weizmann Institute of Science, Rehovot, Israel for his postdoc and Senior Internship from 2012 to 2023. His goal was to decipher the roles of the importin family of nuclear transport factors in mouse behaviors and neuronal pathways. Using a comprehensive battery of approaches from behavior to molecular mechanisms, his research shed light on the roles for importin α5 in the regulation of anxiety via control of nuclear shuttling of MeCP2 and of other importins and transcription factors in pain and memory.
Nicolas recently launched a new group at the Saints-Pères Paris Institute for the Neurosciences (SPPIN) of the CNRS. He will present his main research achievements and will outline planned future directions in the study of the role of nuclear transport factors in neurodevelopmental disorders. The lab’s priority is to dissect the basic rules of importin α-MeCP2’s interaction and transport dynamics using behavioral analyses, imaging of MeCP2 nuclear shuttling, and testing how modulation of MeCP2 transport can help to rescue phenotypes associated with MeCP2-related disorders such as Rett and MeCP2 duplication syndromes.
Key publications
State-of-the-art therapies for Rett syndrome.
Panayotis N, Ehinger Y, Felix MS, Roux JC. Dev Med Child Neurol. 2023 Feb;65(2):162-170. doi: 10.1111/dmcn.15383. Epub 2022 Sep 3. PMID: 36056801
β-sitosterol reduces anxiety and synergizes with established anxiolytic drugs in mice.
Panayotis N, Freund PA, Marvaldi L, Shalit T, Brandis A, Mehlman T, Tsoory MM, Fainzilber M. Cell Rep Med. 2021 May 18;2(5):100281. doi: 10.1016/j.xcrm.2021.100281. eCollection 2021 May 18. PMID: 34095883
Importin α3 regulates chronic pain pathways in peripheral sensory neurons.
Marvaldi L, Panayotis N, Alber S, Dagan SY, Okladnikov N, Koppel I, Di Pizio A, Song DA, Tzur Y, Terenzio M, Rishal I, Gordon D, Rother F, Hartmann E, Bader M, Fainzilber M. Science. 2020 Aug 14;369(6505):842-846. doi: 10.1126/science.aaz5875. PMID: 32792398
Importin α5 Regulates Anxiety through MeCP2 and Sphingosine Kinase 1.
Panayotis N, Sheinin A, Dagan SY, Tsoory MM, Rother F, Vadhvani M, Meshcheriakova A, Koley S, Marvaldi L, Song DA, Reuveny E, Eickholt BJ, Hartmann E, Bader M, Michaelevski I, Fainzilber M. Cell Rep. 2018 Dec 11;25(11):3169-3179.e7. doi: 10.1016/j.celrep.2018.11.066. PMID: 30540948 Free PMC article.
Macromolecular transport in synapse to nucleus communication.
Panayotis N, Karpova A, Kreutz MR, Fainzilber M. Trends Neurosci. 2015 Feb;38(2):108-16. doi: 10.1016/j.tins.2014.12.001. Epub 2014 Dec 19. PMID: 25534890