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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

Events

On 12/132021

Réseau d'Imagerie de Strasbourg et région Grand-Est first online meeting

The first meeting of the Réseau d'Imagerie de Strasbourg et région Grand-Est (RISE) takes place on Monday 13 December, online. Its aim will be to…

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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    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/AvenirINSERM

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)

Resources

Short videos on the activity of the lab:

 

Cordées de la réussite : Presentation of women in science 

 

Kif21B project presented by José Rivera Alvarez

 

University of Strasbourg 

 

 

 

 

 

 

 

 

 

Publications