Our research is centered on the physiological functions of homeoprotein intercellular transfer, a novel signaling mechanism discovered by our group. We are using molecular and genetic approaches to explore basic and translational aspects of these signaling transcription factors.
Basic aspects
Brain plasticity critical periods
During infancy, childhood, and adolescence, experience and environment shape neural circuits that form the basis of adult perception and behavior. Brain circuits adapt in function of sensory, motor and social stimulation during cascading critical periods of heightened plasticity after which circuitry becomes consolidated. A number of neurodevelopmental disorders, including amblyopia, autism spectrum disorders, and schizophrenia, have now been linked to abnormalities in such experience-driven brain pathways.
The OTX2 homeoprotein regulates the opening and closure of critical periods within visual, auditory, and prefrontal cortices. OTX2 is secreted by the choroid plexus into the cerebrospinal fluid and is transferred specifically into parvalbumin (PV) GABAergic interneurons across cortices. These PV cells drive critical period onset and participate in the consolidation of circuitry. We are pursuing several projects at the epigenetic, transcriptional, and behavioral level in mice to understand how OTX2 regulates PV cell activity and how early-life stress affects the quality of critical periods.
Translational aspects
Eye diseases
The OTX2 homeoprotein is expressed in several cell types within the adult retina and transfers between cells to regulate cell survival and physiology. For example, OTX2 transfers from bipolar cells to retinal ganglion cells, which are the projection neurons from the eye to the brain and their loss results in visual impairment in diseases such as glaucoma and diabetic neuropathy. In mice, ocular injection of OTX2 protein can protect these cells from degeneration. In the LabCom context, we are developing strategies to deliver OTX2 (protein or gene) to the eye to promote cell survival and activity.
Parkinson disease
The EN1 homeoprotein is expressed by mesencephalic dopaminergic neurons and exerts a maintenance effect on their heterochromatin structure that enables their survival in rodent and non-human primate models of Parkinson diseases. In the LabCom context, we are developing protein and gene delivery approaches to target EN1 to dopamine neurons for Parkinson disease therapy.
Amyotrophic Lateral Sclerosis
The EN1 homeoprotein is expressed by spinal cord interneurons (ventral in rodents, anterior in humans) and is transferred into motoneurons where it acts as a neurotrophic agent. In the LabCom context, we are exploring the use of EN1 as therapeutic homeoprotein in ALS.
Collaborations
Local within the CIRB
L. Venance, N. Rouach
National
J.M. Mallet (ENS Paris), R. Daniel (Evry U), C. Théry (Institut Curie), M.O. Krebs (CPNP Paris), D. Loew (Institut Curie), S. Nedelec (Inserm), T. Lamonerie (iBV, Nice)
International
D. Geschwind (UCLA, USA), T. Hensch (Harvard U, USA), B. Sorg (Washingtion State U, USA), A. Van Der Linden (Antwerp U, Belgium), E. Hedlund (Stockholm U, Sweden), L. Van den Bosch (U of Leuven, Belgium), H. Okano (Keio U, Tokyo, Japan).
