Genetics of mouse brain development

The aims of our work are to elucidate the key mechanisms of neurogenesis in the developing and post-natal cerebral cortex. During corticogenesis, the remarkable array of different neuronal cell types is generated from a complex population of multipotent stem and progenitor cells following a precise spatial and temporal pattern before being assemble in maps and circuits. We are interested in understanding the cellular and molecular mechanisms by which these different neuronal cell types are temporally and spatially regulated by the action of defined regionalized and coordinated differentiation programs.

The mammalian cerebral cortex, which is responsible for high-level perceptual analysis and executive functions, is subdivided into a number of functionally individual areas that process distinct sensory modalities and motor outputs. Cortical areas are defined by their pattern of gene expression, cytoarchitecture, and input/output connectivity. Each area is then radially sub-divided into distinct six layers, and each layer consists of neurons with distinctive functions, morphologies, connectivity pattern and a repertoire of transcription factors expressed in different combinations. Since areas are made of layers and layers build up areas, areal and laminar specification become two closely interrelated processes during corticogenesis.

Areal and laminar identity are initially specified in cortical progenitors by a series of regionalised factors, and then implemented through subsequent processes of fate acquisition by other factors expressed in post-mitotic neurons. Our work has demonstrated a major role of the nuclear receptor COUP-TFI in coordinately regulating areal and laminar identity in a temporally-controlled manner in the mouse developing cerebral cortex.

We have showed that during corticogenesis, COUP-TFI is required in balancing the neocortex into frontal/motor and sensory areas ( Armentano et al., Nature Neuroscience, 2007 ), in controlling the generation of corticospinal motor neurons ( Tomassy et al., PNAS, 2010 ), in axonal outgrowth ( Armentano et al., Development, 2006 ) and in neuronal migration ( Alfano et al., Development, 2011 ).


Schematics on the role for COUP-TFI in controlling the balance between motor and sensory aresa. Areas have distinct cytoarchitecture and connectivity. Motor areas have a thick layer V, whereas sensory areas have a thick layer IV. By controlling area patterning COUP-TFI regulates not only layer and cell-type specification, but also cell migration and axonal elongation.

We plan in the next few years to gain more insights into how cortical realization is linked to the mode of progenitor/stem cell division, fate commitment of mitotic and post-mitotic neurons, activity-dependent mechanisms of cortical cells and thalamocortical topography.

We combine several molecular and cellular approaches, including mouse genetics, developmental neuroanatomy, in utero elctroporation, in vitro and biochemical assays, and neural stem cell cultures.

 

GFP-expressing cells (green) electoporated at embryonic day 14.5 have migrated to upper layers in a post-natal day 8 mouse neocortex. Red neurons label subcerebral projection neurons in lower layers .



P8 brains electroporated with a GFP-expressing construct at E14.5. GFP labels migrating neurons and projecting axons, in this case callosal projection neurons, innervating the contralateral side.

 

Last publications

Molecular control of two novel migratory paths for CGE-derived interneurons in the developing mouse brain. - 2016 - Development (Cambridge, England) - Touzot A, Ruiz-Reig N, Vitalis T, and Studer,M

Area-specific development of distinct projection neuron subclasses is regulated by postnatal epigenetic modifications. - 2016 - eLife - 5 - Harb K, Magrinelli E, Nicolas CS, Lukianets N, Frangeul L, Pietri M, Sun T, Sandoz G, Grammont F, Jabaudon D, Studer M, and Alfano,C

Gradient COUP-TFI Expression Is Required for Functional Organization of the Hippocampal Septo-Temporal Longitudinal Axis. - 2016 - Cerebral cortex (New York, N.Y. : 1991) - Flore G, Di Ruberto G, Parisot J, Sannino S, Russo F, Illingworth EA, Studer M, and De Leonibus,E

Postmitotic control of sensory area specification during neocortical development. - 2014 - Nature communications - 5 P5632 - Alfano C, Magrinelli E, Harb K, Hevner RF, and Studer,M

COUP-TFI controls activity-dependent tyrosine hydroxylase expression in adult dopaminergic olfactory bulb interneurons. - 2013 - Development - 140 P4850-9 - Bovetti S, Bonzano S, Garzotto D, Giannelli SG, Iannielli A, Armentano M, Studer M, and De Marchis,S

The nuclear receptors COUP-TF: a long-lasting experience in forebrain assembly. - 2013 - Cell Mol Life Sci - Alfano C, Magrinelli E, Harb K, and Studer,M

Assembly of the auditory circuitry by a Hox genetic network in the mouse brainstem. - 2013 - PLoS Genet - 9 Pe1003249 - Di Bonito M, Narita Y, Avallone B, Sequino L, Mancuso M, Andolfi G, Franz AM, è L, Puelles FM, Rijli M, and Studer,

Hox genes and region-specific sensorimotor circuit formation in the hindbrain and spinal cord. - 2013 - Dev Dyn - 242 P1348-68 - Di Bonito M, Glover JC, and Studer,M

Neocortical arealization: Evolution, mechanisms, and open questions. - 2012 - Dev Neurobiol - Alfano C, and Studer,M

COUP-TFI promotes radial migration and proper morphology of callosal projection neurons by repressing Rnd2 expression. - 2011 - Development - 138 P4685-97 - Alfano C, Viola L, Heng JI, Pirozzi M, Clarkson M, Flore G, De Maio A, Schedl A, Guillemot F, and Studer,M

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Studer Michele
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   Deschaux Olivier
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    October 2015 - M. Studer Team
   1 POST-DOC position 3 year   Closed

    October 2013 - Michèle Studer Team
   CDD 1 an Assistant ingenieur   Closed

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