Michèle Studer PhD Molecular Biology

Course and current status

Since 03/13       Director of Research (DR1) INSERM, Institute of Biology Valrose (iBV), University Côte d’Azur (UCA), Nice, France.

03/09-02/13      Director of Research DR2 Inserm, UMR Inserm U636/UNS, University of Nice Sophia  Antipolis (UNS), Nice, France.

04/01-02/09     Full Investigator, Staff Scientist (Tenured) at Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.

03/00-03/01     Senior Lecturer at the Unit of Neural Development, Institute of Child Health, University College London, London.

03/97-02/00      Lecturer/MRC Research Fellow at the Department of Developmental Neurobiology, King's College, Guy's Campus, London.

10/91-02/97     Post-doctoral Research Fellow at the Division of Developmental Neurobiology, MRC/National Institute for Medical Research, London.

Scientific summary

We are interested in the molecular mechanisms by which neuronal subtypes within cortical layers and across functional domains are specified during development in physiological and pathological conditions. Several transcription factors expressed in distinct prospective areas and cortical subtypes control the specification and connectivity of a given neuronal sub-population, and are fundamental for understanding overall brain activity and assembly leading to proper behaviour. The assembly and maturation of the mammalian brain result from an intricate cascade of highly coordinated developmental events, such as cell proliferation, migration, and differentiation. Any impairment of this sequentially multi-factorial process can lead to complex neurodevelopmental diseases, sharing common pathogenic mechanisms and molecular pathways resulting in multiple clinical signs.

The team focuses on the relationships between impaired cortical development, malformations and consequent symptoms in neurodevelopmental disorders, as well as the genes implicated in these processes. BBSOAS (Boonstra-Bosch-Schaff Optic Atrophy Syndrome) is a recently described monogenic neurodevelopmental disorder caused by the haploinsufficiency of NR2F1 gene, a transcriptional regulator playing key roles during brain development. Although intellectual disability, developmental delay and visual impairment are the most common symptoms affecting BBSOAS patients, multiple additional features are often reported, including epilepsy, autistic traits and hypotonia. The presence of specific symptoms and their variable level of severity might depend on yet to be fully characterized genotype/phenotype correlations.

By employing a whole series of experimental approaches combining complementary methodologies, we are starting to understand the impact of the different mutations on protein stability and cell function. When possible, experimental findings in animal or cellular models have been linked to corresponding features of the human pathology. In the mouse, Nr2f1 plays several functions during cortical development, from subtype areal lamination to maturation of network activity, hippocampal development governing learning behaviours, assembly of the visual system, and finally establishment of cortico-spinal descending tracts regulating motor execution. Being expressed in a high caudal to low rostral gradient, NR2F1 in the mouse and in human tissue exerts its functions in a regionalized manner by locally controlling long-term self-renewal of neural progenitor cells via modulation of cell cycle genes and key cortical development master genes, such as Pax6, and affecting local degrees of neurogenic activity. In the human foetal cortex, distinct NR2F1 expression levels encompass gyri and sulci and correlate with local degrees of neurogenic activity. In addition, reduced NR2F1 levels in cerebral organoids affect neurogenesis and PAX6 expression. We thus propose NR2F1 as an area-specific regulator of mouse and human brain morphology and a novel causative gene of abnormal gyrification. Overall, our data shed new insights into the cellular and molecular pathophysiological mechanisms of cortical malformations underlying intellectual disability. 

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