|
Deciphering the role of Importins Nuclear Transport Factors in CNS Functions and Neurodevelopmental Disorders| title | Deciphering the role of Importins Nuclear Transport Factors in CNS Functions and Neurodevelopmental Disorders |
|---|
| start_date | 2024/03/08 |
|---|
| schedule | 11h30 |
|---|
| online | no |
|---|
| location_info | / |
|---|
| summary | 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. |
|---|
| responsibles | Perrais, Thoumine |
|---|
Workflow history| from state (1) | to state | comment | date |
|---|
| submitted | published | | 2024/02/29 15:22 UTC |
| |
|