
Regulation of cortical development in health and disease
Regulation of cortical development in health and disease
Our lab aims to elucidate the fundamental mechanisms that dictate cell fate acquisition and neuronal maturation during mammalian corticogenesis.
Main interests
Understand the origin of neuronal diversity in the mouse developing cortex
Study post-transcriptional mechanisms that regulate gene expression during cerebral cortex neurogenesis
Investigate the role of cytoskeleton proteins during cortical development
Interpret the pathological mechanisms of associated neurodevelopmental disorders
Understand the sensitivity of the brain to tRNAs defects.
Strategy
To unravel new regulators of neurodevelopment, we learn from the genetic mutations that have been associated to neurodevelopmental disorders (NDDs), including malformations of cortical development, intellectually disability and epilepsy. Although the etiologies of those diseases are not always clearly understood, the nature of the mutated genes can give us pathological insights and may elucidate general principles for brain development.
Current projects
1. Translational Control of Neuronal Fate and Identity
The cerebral cortex is a central structure of the mammalian brain, characterized by a remarkable diversity of neuronal types. Understanding the origin of the extraordinary neuronal diversity is fundamental to understanding how the cortical architecture and its diverse functions emerge during development. It remains a critical challenge in cellular and molecular neurobiology. While the efforts have been focused on transcriptional control, evidence for regulation at the translational level is emerging. We hypothesize that translational control, though oft overlooked, acts in a combinatorial fashion with transcriptional induction to regulate gene expression programs during cortical patterning. We have demonstrated an intimate functional link between cortical development and cellular content of mature transfer RNA (tRNAs) (Laguesse et al, Dev cell, 2015), the major determinant of translation. We, therefore, propose to address how translational control, through the modulation of the availability of mature translationally competent tRNAs, hones gene expression programs during lineage progression, thereby regulating neuronal diversity. Studying this yet unexplored question could unravel a hitherto unrecognized level of neuronal fate identity determination in the cerebral cortex
We are combining ribosome profiling, mRNA and tRNA deep sequencing and gene manipulation in vivo in the mouse embryonic cortex to i) uncover the specific translational programs that influence neuronal lineages progression; ii) determine how tRNA repertoires (both at the transcriptional and post-transcriptional levels; i.e. tRNAs modification) are shaped to meet the specific translational needs of different cell types during corticogenesis and iii) validate the functional importance of fluctuation in mature tRNA content during cortical development.
2. Regulation of the intracellular dynamics during cortical development
The formation of the nervous system requires functional Microtubules (MTs) and Actin cytoskeletonsduring all stages of development. MTs and actin act in concert with MTs associated proteins (MAPs) and motors and actin binding proteins, respectively, to carry out the structural changes that underpin key developmental events. These include such as neurogenesis, neuronal migration, axon path finding and synapse formation. Interestingly mutations in human genes encoding either tubulin, MAPs or motors have been associated to malformation of cortical development (MCD), a group of socially-devastating neurodevelopmental disorders that can lead to severe intellectual disabilities (ID). However, how these mutations lead to MCD is not fully understood. A better understanding of the role of cytoskeleton proteins during cortical development is critical to shed more light on molecular mechanisms underlying neurodevelopmental pathologies. We approach those issues through a candidates-based approach. Thanks to collaboration with clinicians, we select cytoskeletons associated genes in which variants have been identified in patients presenting with MCD or other neurodevelopmental disorders (NDDs) and whose function is not known in the developing cortex.
We study both the physiological roles of those genes with the aim to identify new regulators of the cortical development and the pathological mechanisms associated to disease to better understand the etiology of NDDs. Our deep functional analysis should allow us to uncover both the cellular and molecular mechanismsunderlying the physiological and pathological function of those newly-discovered genes. We are currently focusing on two genes encoding a kinesin, KIF21b (Asselin et al, Nat com, 2020) and a MT-associated protein WDR47 (Kannan et al, PNAS, 2017).
Members
Researchers
Former members
2018-2021: Hakima FLICI TEZKRATT – PostDoc FRM
2021: Claire RICHARD – Master 1 Student ; University of Strasbourg
2020: Romain CESBRON – Master 1 Student ; University of Strasbourg
2019: Oktay CAKIL – IGBMC Master 1 Summer intern
2019: Karla SORIA ZAVALA – France-Mexico cooperation program - Master 1 intern
2016-2020: Jordi DEL POZO RODRIGUEZ – PhD Student (now Clarivate Analytics)
2015-2019: Laure ASSELIN – PhD Student (now Kaly-Cell)
2017: Théa BEGEL – 2nd year BTS Student ; University of Strasbourg
2017: Mourat VEZIR – IGBMC Master 1 Summer intern
2017: Eloise COLNOT – Master 1 Student ; University Claude Bernard – Lyon
2016: Noémie LELIEVRE – Master 1 Student ; University of Strasbourg
2016: Viviane NGUEFACK NGOUNE – Master 1 Student ; University of Strasbourg
2016: Arthur RADOUX – 2nd year Student ; University of Strasbourg
2015: Morgane FONTAINE – Master 2 Student ; University of Strasbourg
News

Understanding gene regulation during cortical development
At the start of 2022, Juliette Godin, Inserm researcher, won an ERC Consolidator grant for her project "Gene regulation during cortical development".…
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Events
On
06/202023
9th Tri-Regional stem cell & developmental biology meeting
in-person only at IGBMC's auditorium Abstract submission deadline: May 22nd for short talk; June 5th for posters Keynote speakers :-Dr…
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Collaborations and networks
Member of the STRAS&ND Network : Strasbourg Translational Research on the Autism Spectrum Disorder & Neurodevelopmental Disorders
Member of the French Scientific Interest Group on neurodevelopmental disorders and autism
Member of “International Research consortium for the Corpus callosum and cerebral connectivity”.
Member of RISE, Network of all the imaging platforms of Strasbourg
Member, Research Network “DRN club” (development of neuronal circuits) - FR http://www.ibdm.univ-mrs.fr/drn/index.php?page=board
Funding and partners
2022 ERC Consolidator grant
2022 Fondation pour la recherche sur le cerveau- Rotary Espoir en tête
2022 ANR PRC Synovar
2022 4th year PhD fellowship (J. River Alvarez) - FRM (Fondation pour la Recherche Médicale)
2021 PhD fellowship (P. Tilliole), Université de Strasbourg
2021 ANR PRC InotRNA
2019 ANR PRCI TempoCorticoDev
2019 PhD fellowship ( C. Hardion), IDEX, Université de Strasbourg
2018 ANR PRCE DyrkDOWN
2018 ANR PRC NEDD4L-MCD
2016 4th year PhD fellowship (J. Del Pozo) - ARC (Association pour la recherche sur le cancer)
2018 Post-doct. fellowship to H. Flici from FRM (Fondation pour la Recherche Médicale)
2018 Research grant from Fondation Jérome Lejeune
2018 4th year PhD fellowship (L. Asselin) - FRM (Fondation pour la Recherche Médicale)
2016 PhD fellowship (J. Del Pozo) - INSERM/ Region Grand Est
2016 Research grant Idex, Université de Strasbourg
2015 Research grant - Fondation Fyssen
2015 ATIP/Avenir– INSERM
2014 ANR starting grant (young researcher program)
Awards and recognitions
2020 Prix Espoir University of Strasbourg (https://recherche.unistra.fr/index.php?id=31268)
2019 Prix Wallach - Académie d’Alsace des Sciences, Lettres et Arts
2012 Post-doctoral fellowship to J. Godin from Marie Curie Action – FP7-PEOPLE-2010-IEF
2011 Post-doctoral long term fellowship to J. Godin from EMBO – ALTF-1031-2010
2010 Post-doctoral fellowship from FRM (Fondation pour la Recherche Médicale)
Publications
2021
The structure of the mouse ADAT2/ADAT3 complex reveals the molecular basis for mammalian tRNA wobble adenosine-to-inosine deamination
- Elizabeth Ramos Morales
- Efil Bayam
- Jordi del Pozo Rodriguez
- Thalia Salinas-Giegé
- Martin Marek
- Peggy Tilly
- Philippe Wolff
- Edouard Troesch
- Eric Ennifar
- Laurence Drouard
- Juliette Godin
- Christophe Romier
Nucleic Acids Research ; Volume: 49 ; Page: 6529-6548
2020
Mutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity
- Laure Asselin
- José Rivera Alvarez
- Solveig Heide
- Camille Bonnet
- Peggy Tilly
- Hélène Vitet
- Chantal Weber
- Carlos Bacino
- Kristin Baranaño
- Anna Chassevent
- Amy Dameron
- Laurence Faivre
- Neil Hanchard
- Sonal Mahida
- Kirsty Mcwalter
- Cyril Mignot
- Caroline Nava
- Agnès Rastetter
- Haley Streff
- Christel Thauvin-Robinet
- ...
Nature Communications ; Volume: 11
2019
TUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis
- Ekaterina Ivanova
- Johan Gilet
- Vadym Sulimenko
- Arnaud Duchon
- Gabrielle Rudolf
- Karen Runge
- Stephan Collins
- Laure Asselin
- Loic Broix
- Nathalie Drouot
- Peggy Tilly
- Patrick Nusbaum
- Alexandre Vincent
- William Magnant
- Valerie Skory
- Marie-Christine Birling
- Guillaume Pavlovic
- Juliette Godin
- Binnaz Yalcin
- Yann Hérault
- ...
Nature Communications ; Volume: 10 ; Page: 100-110
TUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis
- Ekaterina L Ivanova
- Johan Gilet
- Vadym Sulimenko
- Arnaud Duchon
- Gabrielle Rudolf
- Karen Runge
- Stephan Collins
- Laure Asselin
- Loic Broix
- Nathalie Drouot
- Peggy Tilly
- Patrick Nusbaum
- Alexandre Vincent
- William Magnant
- Valérie Skory
- Marie-Christine Birling
- G Pavlovic
- Juliette D Godin
- Binnaz Yalcin
- Yann Hérault
- ...
Nature Communications ; Volume: 10
2018
p27Kip1 Modulates Axonal Transport by Regulating α-Tubulin Acetyltransferase 1 Stability
- Giovanni Morelli
- Aviel Even
- Ivan Gladwyn-Ng
- Romain Le Bail
- Michal Shilian
- Juliette D. Godin
- Elise Peyre
- Bassem A Hassan
- Arnaud Besson
- Jean-Michel Rigo
- Miguel Weil
- Bert Brône
- Laurent Nguyen
Cell Reports ; Volume: 23 ; Page: 2429 - 2442
Ciliogenesis and cell cycle alterations contribute to KIF2A-related malformations of cortical development
- Loïc Broix
- Laure Asselin
- Carla Silva
- Ekaterina Ivanova
- Peggy Tilly
- Johan Gilet
- Nicolas Lebrun
- Hélène Jagline
- Giuseppe Muraca
- Yoann Saillour
- Nathalie Drouot
- Madeline Louise Reilly
- Fiona Francis
- Alexandre Benmerah
- Nadia Bahi-Buisson
- Richard Belvindrah
- Laurent Nguyen
- Juliette Godin
- Jamel Chelly
- Maria-Victoria Hinckelmann
Human Molecular Genetics ; Volume: 27 ; Page: 224-238
2017
WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy
- Meghna Kannan
- Efil Bayam
- Christel Wagner
- Bruno Rinaldi
- Perrine Kretz
- Peggy Tilly
- Marna Roos
- Lara Mcgillewie
- Séverine Bär
- Shilpi Minocha
- Claire Chevalier
- Chrystelle Po
- Jamel Chelly
- Jean-Louis Mandel
- Renato Borgatti
- Amélie Piton
- Craig Kinnear
- Ben Loos
- David Adams
- Yann Herault
- ...
Proceedings of the National Academy of Sciences of the United States of America ; Volume: 114 ; Page: E9308-E9317
2016
Mutations in the HECT domain of NEDD4L lead to AKT–mTOR pathway deregulation and cause periventricular nodular heterotopia
- Loic Broix
- Hélène Jagline
- Ekaterina L Ivanova
- Stéphane Schmucker
- Nathalie Drouot
- Jill Clayton-Smith
- Alistair T. Pagnamenta
- Kay Metcalfe
- Bertrand Isidor
- Ulrike Walther Louvier
- Annapurna Poduri
- Jenny Taylor
- Peggy Tilly
- Karine Poirier
- Yoann Saillour
- Nicolas Lebrun
- Tristan Stemmelen
- Gabrielle Rudolf
- Giuseppe Muraca
- Benjamin Saintpierre
- ...
Nature Genetics ; Volume: 48 ; Page: 1349-1358
Mutations in the HECT domain of NEDD4L lead to AKT–mTOR pathway deregulation and cause periventricular nodular heterotopia
- Hélène Jagline
- Ekaterina L Ivanova
- Stéphane Schmucker
- Nathalie Drouot
- Jill Clayton-Smith
- Alistair Pagnamenta
- Kay Metcalfe
- Bertrand Isidor
- Ulrike Walther Louvier
- Annapurna Poduri
- Jenny Taylor
- Peggy Tilly
- Karine Poirier
- Yoann Saillour
- Nicolas Lebrun
- Tristan Stemmelen
- Gabrielle Rudolf
- Giuseppe Muraca
- Benjamin Saintpierre
- Adrienne Elmorjani
- ...
Nature Genetics ; Volume: 48 ; Page: 1349-1358
Real‐time Recordings of Migrating Cortical Neurons from GFP and Cre Recombinase Expressing Mice
- Sylvia Tielens
- Juliette Godin
- Laurent Nguyen
Current Protocols in Neuroscience ; Volume: 74