Prochiantz & Di Nardo

Development and Neuropharmacology/LabCom team

Principal Investigators: Ariel DI NARDO, CRCN CNRS & Alain PROCHIANTZ, Pr. Em. Collège de France and BrainEver CSO

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)

Selected Publication 2016-2021

- Arnaud, K., Oliveira Moreira, V., Vincent, J., Dallerac, G., Dubreuil, C., Dupont, E., Richter, M., Müller, U.C., Rondi-Reig, L., Prochiantz, A., et al. (2021). Choroid plexus APP regulates adult brain proliferation and animal behavior. Life Sci Alliance 4, e202000703.

- Ibad, R.T., Quenech’du, N., Prochiantz, A., and Moya, K.L. (2022). OTX2 stimulates adult retinal ganglion cell regeneration. Neural Regen Res 17, 690–696.

- Planques, A., Oliveira Moreira, V., Benacom, D., Bernard, C., Jourdren, L., Blugeon, C., Dingli, F., Masson, V., Loew, D., Prochiantz, A., et al. (2021). OTX2 Homeoprotein Functions in Adult Choroid Plexus. Int J Mol Sci 22, 8951.

- Vincent, C., Gilabert-Juan, J., Gibel-Russo, R., Alvarez-Fischer, D., Krebs, M.-O., Le Pen, G., Prochiantz, A., and Di Nardo, A.A. (2021). Non-cell-autonomous OTX2 transcription factor regulates anxiety-related behavior in the mouse. Mol Psychiatry.

- Harkness, J.H., Gonzalez, A.E., Bushana, P.N., Jorgensen, E.T., Hegarty, D.M., Di Nardo, A.A., Prochiantz, A., Wisor, J.P., Aicher, S.A., Brown, T.E., et al. (2021). Diurnal changes in perineuronal nets and parvalbumin neurons in the rat medial prefrontal cortex. Brain Struct Funct.

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Devienne, G., Picaud, S., Cohen, I., Piquet, J., Tricoire, L., Testa, D., Di Nardo, A.A., Rossier, J., Cauli, B., and Lambolez, B. (2021). Regulation of perineuronal nets in the adult cortex by the activity of the cortical network. J Neurosci JN-RM-0434-21.

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Ravel-Godreuil, C., Massiani-Beaudoin, O., Mailly, P., Prochiantz, A., Joshi, R.L., and Fuchs, J. (2021). Perturbed DNA methylation by Gadd45b induces chromatin disorganization, DNA strand breaks and dopaminergic neuron death. IScience 24, 102756.

- Kaddour, H., Coppola, E., Di Nardo, A.A., Le Poupon, C., Mailly, P., Wizenmann, A., Volovitch, M., Prochiantz, A., and Pierani, A. (2020). Extracellular Pax6 Regulates Tangential Cajal-Retzius Cell Migration in the Developing Mouse Neocortex. Cereb Cortex 30, 465–475.

- Amblard, I., Thauvin, M., Rampon, C., Queguiner, I., Pak, V.V., Belousov, V., Prochiantz, A., Volovitch, M., Joliot, A., and Vriz, S. (2020). H2O2 and Engrailed 2 paracrine activity synergize to shape the zebrafish optic tectum. Communications Biology 3, 536.

- Torero-Ibad, R., Mazhar, B., Vincent, C., Bernard, C., Dégardin, J., Simonutti, M., Lamonerie, T., Di Nardo, A., Prochiantz, A., and Moya, K.L. (2020). OTX2 non-cell autonomous activity regulates inner retinal function. ENeuro.

- Vargas Abonce, S.E., Leboeuf, M., Prochiantz, A., and Moya, K.L. (2019). Homeoprotein neuroprotection of embryonic neuronal cells. ENeuro 7.

- Planques, A., Oliveira Moreira, V., Dubreuil, C., Prochiantz, A., and Di Nardo, A.A. (2019). OTX2 Signals from the Choroid Plexus to Regulate Adult Neurogenesis. ENeuro 7;6(2).

- Thomasson, N., Pioli, E., Friedel, C., Monseur, A., Lavaur, J., Moya, K.L., Bezard, E., Bousseau, A., and Prochiantz, A. (2019). Engrailed-1 induces long-lasting behavior benefit in an experimental Parkinson primate model. Mov. Disord.

- Blaudin de Thé, F.-X., Rekaik, H., Peze-Heidsieck, E., Massiani-Beaudoin, O., Joshi, R. L., Fuchs, J. & Prochiantz, A. (2018). Engrailed homeoprotein blocks degeneration in adult dopaminergic neurons through LINE-1 repression. EMBO J. 37

- Apulei, J., Kim, N., Testa, D., Ribot, J., Morizet, D., Bernard, C., Jourdren, L., Blugeon, C., Di Nardo, A. A. & Prochiantz, A. (2018), Non-cell Autonomous OTX2 Homeoprotein Regulates Visual Cortex Plasticity Through Gadd45b/g. Cereb. Cortex. 29 (6): 2384-2395.

- Lee, H. H. C., Bernard, C., Ye, Z., Acampora, D., Simeone, A., Prochiantz, A., Di Nardo, A. A., & Hensch, T. K., (2017), Genetic Otx2 mis-localization delays critical period plasticity across brain regions. Mol. Psychiatry 22, 680–688.

- Bernard, C., Vincent, C., Testa, D., Bertini, E., Ribot, J., Di Nardo, A. A., Volovitch M., & Prochiantz, A. (2016), A Mouse Model for Conditional Secretion of Specific Single-Chain Antibodies Provides Genetic Evidence for Regulation of Cortical Plasticity by a Non-cell Autonomous Homeoprotein Transcription Factor. PLoS Genet. 12, e1006035.

Preprint
- Abonce, S.E.V., Lebœuf, M., Moya, K.L., and Prochiantz, A. (2020). The homeoprotein ENGRAILED-1 promotes motoneuron survival and motor functions. bioRxiv

Reviews
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Moya, K.L., and Ibad, R.T. (2021). OTX2 signaling in retinal dysfunction, degeneration and regeneration. Neural Regen Res 16, 2002–2003.

- Di Nardo, A.A., Joliot, A., and Prochiantz, A. (2020). Homeoprotein transduction in neurodevelopment and physiopathology. Sci Adv 6, eabc6374.

- Testa, D., Prochiantz, A., and Di Nardo, A.A. (2019). Perineuronal nets in brain physiology and disease. Semin. Cell Dev. Biol. 89, 125–135.

- Di Nardo, A.A., Fuchs, J., Joshi, R.L., Moya, K.L., and Prochiantz, A. (2018). The Physiology of Homeoprotein Transduction. Physiol. Rev. 98, 1943–1982.

- Arnaud, K. & Di Nardo, A.A. (2016). Choroid plexus trophic factors in the developing and adult brain. Front. Biol. 11, 214–221.

- Prochiantz, A. (2018). How to navigate counter dogmatic research findings. EMBO J. 37.

- Blaudin de Thé, F.-X., Rekaik, H., Prochiantz, A., Fuchs, J., and Joshi, R.L. (2016). Neuroprotective Transcription Factors in Animal Models of Parkinson Disease. Neural Plast. 2016, 6097107.

- Kim, H.-T., Prochiantz, A., and Kim, J.W. (2016). Donating Otx2 to support neighboring neuron survival. BMB Rep 49, 69–70.

- Bernard, C., and Prochiantz, A. (2016). Otx2-PNN Interaction to Regulate Cortical Plasticity. Neural Plast. 2016, 7931693.

Editorials
- Germain, S., and Di Nardo, A.A. (2019). Editorial: Matrix Proteins. Semin. Cell Dev. Biol. 89, 99.

Book Chapters
- Prochiantz A. & Di Nardo A. A. Shuttling homeoproteins and their biological significance. In: Langel Ü. (eds) Cell Penetrating Peptides. Methods in Molecular Biology, vol 2383. Humana, New York, NY. (2022)

Books
- Prochiantz, A. Singe toi-même. Editions Odile Jacob, Paris (2019).

People

Group leaders:
Di Nardo Ariel, CRCN CNRS
Prochiantz Alain, Pr. Em. Collège de France

Senior researchers:
Moya Kenneth, DR2 CNRS
Di Lullo Elizabeth, BrainEver

Postdoctoral fellows & PhD Students:
Leboeuf Melanie, Postdoc BrainEver
Vargas Stephanie, Postdoc BrainEver
Valverde Sébastien, Postdoc BrainEver
Benacom David, PhD student
Gassama Salimata, PhD student
Gibel-Russo Rachel, PhD student

Technical staff:

Queguiner Isabelle, IE CDF
Angélique Bibimbou, BrainEver
Lucía Jiménez Alonso, BrainEver