The role of transcription factor Neurod2 in cortex development and its implications in neurodevelopmental disorders

Karen Runge

Cardoso-Represa Lab

Cirtucal Development

 

Abstract

The neuronal transcription factor NEUROD2 is an activity-dependent bHLH that is strongly expressed in cortical projection neurons from early development onwards. NEUROD2 has been associated with synaptic integration in hippocampus and with development of the barrel cortex. Recently, genetic variants have been identified in patients with epilepsy and neurodevelopmental delay which makes NEUROD2 a new candidate for neurodevelopmental disorders.

I aimed to study how deletion of Neurod2 in mice affects the development of the cerebral cortex. Using a variety of approaches, I and my team found that cortical projection neurons in Neurod2 KO embryos over-migrate, thereby altering the final size and position of cortical layers. In juvenile and adults, dendritic spine density and turnover are dysregulated in apical but not basal compartments of layer 5 neurons. Functionally, patch-clamp recordings in layer 5 neurons of juvenile mice reveal increased intrinsic excitability. Molecularly, bulk RNA sequencing showed dysregulated expression of many genes associated with neuronal excitability and synaptic function, whose human orthologs are strongly associated with autism spectrum disorders (ASD). Finally, at the behavioral level, Neurod2 KO mice and conditional Neurod2 forebrain-deleted mice display social interaction deficits with hyperactivity, stereotypies and occasional seizures. Taking these observations into account we were able to identify eleven patients with pathogenic NEUROD2 mutations that were diagnosed with ASD and intellectual disability pointing thus to a crucial role of NEUROD2 in cortical development.

In sum, I performed a thorough reverse genetic study, which points to NEUROD2 as a hub gene that regulates various neuronal processes from embryonic neuronal migration to synaptic function and spine turnover in adulthood, whose alterations drive neurodevelopmental disorders, like ASD, epilepsy and intellectual disability.

 

Jury
CARDOSO Carlos, Co-directeur de thèse – Inmed, Marseille

DE CHEVIGNY Antoine, Co-directeur de thèse – Inmed, Marseille

GODIN Juliette, Rapportrice – IGBMC, Illkirch-Graffenstaden

PIERANI Alessandra, Rapportrice – Institut Imagine, Paris

PACARY Emilie, Examinatrice – Neurocentre Magendie, Bordeaux

ROUX, Jean-Christophe, Président – Marseille Medical Genetics

 

Inmed meeting room, Tuesday, May 24th, 2022, 2 pm

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