équipe Féron

Our topics

Neurogenesis

Neurogenesis is the main and central research topic of the team. Which epigenetic modification can explain the altered neurogenesis shown in adult animals exposed pre/postnatally to olfactory cue or nutritional deficiency ? What are the molecular mechanisms underlying the abnormal neurogenesis observed in neurodevelopmental disorders such as autism ? What role do immune molecules play in the permanent neurogenesis observed in the olfactory system ? How can olfactory stem and ensheathing cells increase neurogenesis in patients suffering from neurodegenerative diseases or affected by a spinal cord trauma ? These are some of the questions we are aiming to answer to. The studies performed currently by the team can be classified into two subcategories : A) Imprinting and brain development ; B) Olfactory neurogenesis and brain repair.

Lab members

- François Féron, Professor, Group leader
- Madeleine Erard-Garcia, Researcher INSERM
- El Chérif Ibrahim, Researcher CNRS
- Jean Jacques Remy, Researcher INRA
- John Bianco, Post-doc
- Andrea Abreu, PhD student
- Olivier Alluin, PhD student
- Raoul Belzeaux, Médecin, student
- Jean François Chabas, Médecin, student
- Emmanuel Nivet, PhD student

A-Imprinting and brain development

1.Olfactory imprinting in C. Elegans (Jean Jacques Remy)

Olfactory imprinting is a process in which the exposure of animals to olfactory cues during specific and restricted time windows leaves a permanent memory ("olfactory imprint") that shapes the animal’s behavior upon encountering the olfactory cues at later times. We found that Caenorhabditis elegans displays olfactory imprinting behavior that is mediated by a single pair of interneurons. We currently study the molecular mechanisms underlying this olfactory imprinting (http://elegans.swmed.edu/).

- Collaborators
Oliver Hobert, Columbia University, New York, USA. http://cpmcnet.columbia.edu/dept/gsas/biochem/labs/hobert/index.html
- Recent publication
Rémy JJ and Hobert O (2005) An interneuronal chemoreceptor required for olfactory imprinting in C. elegans. Science, 29 July, 309 : 787-790.
- Funding INRA, CNRS

2.Maternal hypovitaminosis D and Multiple Sclerosis (Andrea Abreu, El Chérif Ibrahim, François Féron)

Both genetic and environmental factors contribute to the risk of developing multiple sclerosis (MS). Epidemiological studies identify low prenatal Vitamin D as potentially a major risk. Previously, we demonstrated that low prenatal vitamin D adversely affects neurogenesis and brain development in neonate and adult rats. Currently, we assess whether a maternal depletion of vitamin D alters the immunological tolerance of the offspring and makes it more susceptible to multiple sclerosis.

- Collaborators
Darryl Eyles, Tom Burne, John McGrath, University of Queensland, Brisbane, Australia. http://www.qcsr.uq.edu.au/devneuro.htm
Frédéric Jehan, Michèle Garabedian, Inserm U561, Hôpital Saint-Vincent de Paul, Paris. http://www.gc2id-univ-paris5.org/EAD/folder.2005-05-23.6874454945/ead.2005-06-01.3364480019
François Roman, Université Aix Marseille I, Marseille. http://www.up.univ-mrs.fr/document.php?project=umr_6149&locale=fr&level1=660adb5b66fe133282eccb86a2ebfbbe&level2=1&doc=eq2_accueil
José Boucraut, NICN, IFR Jean Roche, Marseille.
- Recent publications
Féron F, Burne THJ, Brown J, Smith E, McGrath JJ, Mackay-Sim A, Eyles D (2005) Developmental vitamin D3 deficiency alters the adult rat brain. Brain Res Bull, 65(2) : 141-48.
Burne THJ, Féron F, Brown J, Eyles DW, McGrath JJ and Mackay-Sim A (2004). Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle. Physiology and Behavior, 81(4):651-5.
Mackay-Sim A, Féron F, Eyles D, Burne T and McGrath J (2004). Schizophrenia, vitamin D and brain development. Int Rev Neurobiol., 59:351-80.
McGrath JJ, Féron F, Burne THJ, Mackay-Sim A and Eyles DW (2004). Vitamin D3 and implications for brain development. Journal of Steroid Biochemistry and Molecular Biology 89-90(1-5):557-60.
Eyles D, Brown J, Mackay-Sim A, McGrath J, Féron F. (2003) Vitamin D3 and brain development. Neuroscience, 118 : 641-653.
- Funding ARSEP, CNRS

3. Olfactory neural cells, a diagnostic tool for developmental brain disorders (Raoul Belzeaux, El Chérif Ibrahim, François Féron)

To date, molecular abnormalities in brain diseases have been studied using nervous tissue samples collected post-mortem. However, this material has limitations. Death induces rapid cellular and molecular changes, and studies are biased due to the inevitable variation of the delay between death and sample collection. Diagnostic and demographic data for these cases are often suboptimal. It is also rare that material can be collected from unaffected family members, (e.g. from both members of a discordant monozygotic twin pair). In contrast, the olfactory neuroepithelium located at the back of the nose is a source of tissue closely related to the nervous system, that is available for comprehensive studies. The olfactory epithelium is readily accessible and can be biopsied safely with little discomfort and without any loss of sense of smell. Accordingly, the olfactory epithelium provides an “open window” in the adult human through which one can study cellular and molecular abnormalities that may be associated with developmental brain disorders, such as autism.

- Collaborators
Bruno Gepner, Service Pédo-Psychiatrie, Hôpital Montperrin, Aix en Provence. http://www.lpl.univ-aix.fr/lpl/personnel/staff.htm
Jacques Magnan, Service ORL, Hôpital Nord, Marseille.
Patrick Dessi, Service ORL, Hôpital La Timone, Marseille.
Jean Naudin, Department of Psychiatry, La Timone Hospital, Marseille. http://www.timone.univ-mrs.fr/medecine/recherche/Annuaire/Web/AZORIN_89.htm
- Recent publications
McCurdy RD, Féron F, Perry C, Chant DC, McLean D, Matigian N, Hayward NK, McGrath JJ, Mackay-Sim A. (2005) Cell cycle alterations in biopsied olfactory neuroepithelium in schizophrenia and bipolar I disorder using cell culture and gene expression analyses. Schizophrenia Research (in press).
Perry C, Féron F, Mackay-Sim A, McCurdy R, Hirning M, Chant D, McGrath J. (2002) Olfactory neural cells – An untapped diagnostic and therapeutic resource. Laryngoscope 112(4) : 603-7.
Féron F, Perry C, Wiseman M, Mc Grath J and Mackay-Sim A. (1999) Altered adhesion, proliferation and death in neural cultures from adults with schizophrenia. Schizophrenia Research 40(3) : 211-217.
- Funding Fondation de France, CNRS

B. Olfactory neurogenesis and brain repair

1. Role of MHC molecules in olfactory neurogenesis (El Chérif Ibrahim, Jean Jacques Remy)

The olfactory neuroepithelium is permanently renewed, even in adult humans. It is a good model for studying the factors and molecules involved in neurogenesis as well as in neuron-glia interactions. It has been shown that some molecules of the immune system are expressed in the developing or the pathological brain. We currently study the role of these molecules during olfactory neurogenesis, in control conditions and after a lesion. Furthermore, we investigate the activity-dependent transcription of mRNA pools within the olfactory knobs.

- Collaborators
Robin Reed, Harvard Medical School, Boston, USA. http://cellbio.med.harvard.edu/faculty/reed/
Chris Burge, MIT, Cambridge, USA. http://genes.mit.edu/burgelab/
Pascale Durbec, IBDM, Marseille. http://www.agl.univ-mrs.fr/ibdm.php
Roland Salesse, Marie-Annick Persuy, Neurobiologie de l’olfaction et de la prise alimentaire, INRA, Jouy-en-Josas. http://nopa.jouy.inra.fr/
- Recent publications
Ibrahim EC, Schaal TD, Hertel KJ, Reed R, Maniatis T (2005). Serine/arginine-rich protein-dependent suppression of exon skipping by exonic splicing enhancers. PNAS USA 102 : 5002-5007.
McCurdy R, Féron F, McGrath J, Mackay-Sim A. Regulation of adult olfactory neurogenesis by insulin-like growth factor-I. (2005) Eur. J. Neurosci., 22(7):1581-8.
Ibrahim EC, Guerra N, Terrier-Lacombe MJ, Angevin E, Chouaib S, Carosella ED, Caignard A, Paul P (2001). Tumor specific up-regulation of the nonclassical class I antigen HLA-G expression in renal carcinoma. Cancer Res. 61 : 6838-6845.
Hsu P, Yu F, Féron F, Pickles J, Sneesby K, Mackay-Sim A (2001) Basic fibroblast growth factor and fibroblast growth factor receptors in adult olfactory epithelium. Brain Res. 896(1-2):188-97.
Newman M, Féron F and Mackay-Sim A (2000) Growth factor regulation of neurogenesis in adult olfactory epithelium. Neuroscience 99(2) : 343-350.
Féron F, Vincent A, Mackay-Sim A (1999) Dopamine promotes differentiation of olfactory neuron in vitro. Brain Res. 845(2):252-259.
- Funding INRA, CNRS

2. Cell Therapy

Autologous transplants of olfactory ensheathing cells in animal models of paraplegia and in humans (Olivier Alluin, John Bianco, Jean François Chabas, François Féron)

The olfactory mucosa, located in the nose, is a nervous tissue of great interest. Besides its fundamental role in olfaction, it produces new neurons every day to replace those that are damaged by pollution, viruses etc. Newly formed neurons grow every day, extending new axons that branch their target, the olfactory bulb inside the brain to maintain our sense of olfaction. During this maturation process, the neuron is helped by special glial cells, named olfactory ensheathing cells, which feed and guide its growing axon. We and others have isolated and amplified these ensheathing cells to inject them in the damaged spinal cord of paraplegic rats to assess whether these cells could help sectioned axons to regrow and find their targets allowing at least partial recovery of locomotor function. The experiments on animal models were so promising that we have initiated a world first Phase I clinical trial during which three paraplegic patients have been grafted with their own nasal ensheathing cells. Recently, we have extended the study of these cells in an animal model of peripheral nerve repair.

- Collaborators
Alan Mackay-Sim, Griffith University, Brisbane, Australia. http://www.gu.edu.au/school/bbs/content_mackay.html
Patrick Decherchi, UPRES EA 3285, STAPS, Marseille. http://www.physiologie.staps.univ-mrs.fr/
Pascal Zenatti, Centre de Recherche Hyperbarie Appliquée aux Handicaps, Marseille. http://crhah.perso.cegetel.net/
Guy Magalon, Department of Plastic and Repair Surgery, Université Aix Marseille II, Marseille. http://www.timone.univ-mrs.fr/medecine/recherche/Annuaire/Web/MAGALON_102.htm
Jacques Magnan, Service ORL, Hôpital Nord, Marseille.
Patrick Dessi, Service ORL, Hôpital La Timone, Marseille.
- Recent publications
Féron F, Perry C, Cochrane J, Licina P, Nowitzke A, Urquhart S, Geraghty T and Mackay-Sim A (2005) Autologous olfactory ensheathing cell transplantation in human spinal cord injury. Brain, Oct 11.
Bianco J, Perry C, Harkin D, Mackay-Sim A, Féron F. (2004) Neurotrophin 3 promotes purification and proliferation of olfactory ensheathing cells from human nose. Glia, 45(2) : 111-23.
- Funding AFM, Alarme, Demain Debout, Fondation de l’Avenir, NRJ Foundation, Fondation Intermarché, CNRS

Transplants of olfactory adult stem cells in animal models of cerebral ischemia, amnesia and Huntington disease (Emmanuel Nivet, François Féron)

Interestingly, the olfactory mucosa also includes adult neural stem cells that can be used to repair the damaged nervous system. In the context of an international collaboration, we have developed methods for growing stem cells from mouse, rat and human olfactory mucosa, including from persons with Parkinson’s disease. Stem cells from olfactory epithelium can be induced to differentiate into dopaminergic neurons, the very same neuron type that degenerates to induce Parkinson’s disease. We are currently investigating whether rat olfactory stem cells can be therapeutic in rodent models of Huntington disease, cerebral ischemia and amnesia. The availability of olfactory cells in every individual also means that stem cells can be taken from the patient, purified and expanded in vitro and then transplanted autologously to the damaged area of the CNS.

Transplantation de cellules souches adultes de la muqueuse olfactive dans des modèles animaux d’amnésie, d’ischémie cérébrale et de la maladie de Huntington (Emmanuel Nivet, François Féron)

La muqueuse olfactive contient également des cellules souches neurales qui peuvent être utilisées pour réparer le système nerveux. Dans le contexte d’une collaboration internationale, nous avons développé une méthode pour cultiver les cellules souches olfactives de rat et d’humain, y compris chez des patients atteints de la maladie de Parkinson. Les cellules souches peuvent être différenciées en neurones dopaminergiques et transplantées, différenciées ou non, dans des modèles animaux des maladies de Parkinson et Huntington. Actuellement, nous étudions le devenir des cellules souches olfactives après transplantation dans des modèles rongeurs d’amnésie post-lésionelle et d’ischémie cérébrale. L’accessibilité du tissu olfactif périphérique chez tout être humain rend possibles la collecte de ce tissu et la transplantation autologue de cellules souches adultes dans les aires cérébrales affectées par le traumatisme ou la maladie.

Collaborators
Wayne Murrell, Alan Mackay-Sim, Griffith University, Brisbane, Australia. http://www.gu.edu.au/school/bbs/content_mackay.html
François Roman, Université Aix Marseille I, Marseille. http://www.up.univ-mrs.fr/document.php?project=umr_6149&locale=fr&level1=660adb5b66fe133282eccb86a2ebfbbe&level2=1&doc=eq2_accueil
Jean Philippe Azulay, Department of Neurology and Neuromuscular Diseases, La Timone Hospital, Marseille. http://www.timone.univ-mrs.fr/medecine/recherche/Annuaire/Web/POUGET_47.htm
Jacques Magnan, Service ORL, Hôpital Nord, Marseille.
Patrick Dessi, Service ORL, Hôpital La Timone, Marseille.
Santiago Rivera, Michel Khrestchatisky, NICN, IFR Jean Roche, Marseille.
Société Bioalternatives, Gençay. http://www.bioalternatives.com/pages/1.asp

Recent publications Féron F*, Murrell W*, Wetzig A, Cameron N, Splatt K, Bellette B, Bianco, J, Perry C, Lee G, Mackay-Sim A (2005) Multipotent stem cells from adult olfactory mucosa. Developmental Dynamics, 233(2):496-515 *equally contributing authors

Funding AP-HM, CNRS

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