TEAM

Molecular control of neurogenesis

Group leader : H. Cremer

We study the molecular mechanisms that control the determination of neural stem cells in the mammalian forebrain and the stepwise differentiation and integration of new neurons in the circuitry.

FOR BEGINNERS
Picture of the adult olfactory bulb during neurogenesis by the the Cremer team from IBDM, IBDML

Cross section through the adult olfactory bulb. New neurons (green) are permanently generated by adult neural stem cells. Many of these new neurons use dopamine (red) as their neurotransmitter.

Neurogenesis is not only an embryonic process, but continues in the adult mammalian brain. For example, neural stem cells in the forebrain continue to produce large amounts of new neurons that are integrated into the olfactory bulb. This adult neurogenesis is of particular interest since it allows studying neural stem cell biology as well as neuronal determination, migration and differentiation in a far more accessible manner than in the embryo. Moreover, the fact that the adult brain can generate and integrate new neurons, including such using dopamine as their neurotransmitter, raises hope for the use of adult neurogenesis in cell therapeutic approaches to neurodegenerative diseases. A particular focus of our work lies on the fine tuning of gene expression by microRNAs in the control of these processes. In addition, we use this information to develop new strategies for brain repair in particular in the context of Parkinson’s disease.

FOR SPECIALISTS

Neurogenesis in the olfactory system In defined regions of the mammalian brain neurogenesis proceeds into postnatal and adult stages. One example for such ongoing neurogenesis is the subventricular zone (SVZ) of the forebrain lateral ventricles. Here pre-determined neuronal stem cells generate large amounts of neuronal progenitors. After their amplification these young neurons perform long distance chain migration within the rostral migratory stream (RMS) into the olfactory bulb (OB) where they differentiate into interneurons that use GABA, dopamine and glutamate as their neurotransmitter.

Picture of the SVZ-RMS-OB neurogenic system during neurogenesis by the Cremer Team from IBDM, IBDML

The SVZ-RMS-OB neurogenic system. Neural stem cells in the SVZ generate precursors that migrate in the RMS to reach the OB where they differentiate into neurons (right) (SZV, subventricular zone ; RMS, rostral migratory stream ; OB, olfactury bulb)

Using this experimental system we developed and applied new strategies in order to identify and functionally analyse factors regulating neurogenesis in a systematic and efficient manner. We performed a series of high resolution genetic screens to gain profound insights into gene and microRNA expression in the system in space and time. In parallel, we developed a new method that allows easy and targeted electroporation of transgenes and inhibitory shRNAs into defined neural stem cells in the postnatal and adult SVZ, thereby permitting efficient functional in vivo analyses. Based on these tools we focus on four defined question. 1. How are neural stem cells along the ventricular wall determined to produce neurons with defined neurotransmitter phenotypes, morphologies and connectivity? We found that a complex regulatory interaction between the transcription factor Pax6 and the microRNA miR-7a in neural stem cells is crucial for the generation of dopaminergic neurons in the olfactory bulb. Outgoing from this work we identified a series of other regulatory signals that control neuronal phenotype at the stem cell level. 2. How is long distance migration of neuronal progenitors controlled? Over the past years we showed that the membrane protein NCAM, the secreted factor Reelin and chemokine signaling are critical regulators of defined steps in the migration from the SVZ to the OB. 3. How is terminal neuronal differentiation and integration in the OB regulated? We found that expression of the bHLH transcription factor NeuroD1 is necessary and sufficient to induce terminal neuronal differentiation of adult generated neurons. Moreover, we are investigating microRNA regulation of protein production as a key mechanism in this process. 4. How are new synapses induced and stabilized in the adult brain? We demonstrated that the proteoglycan Agrin, originally considered as an inducer and stabilizer of the neuromuscular junction, is crucial for synapse formation and therefore for the integration and survival new neurons in the adult brain. Based on these studies we identified other signals that either control synapse formation or their function. Finally, the fact that the adult brain can generate and integrate new neurons raised hope for the use of adult neurogenesis in cell therapeutic approaches to neurodegenerative diseases via transplantation or the recruitment of endogenous progenitors. We are exploiting this potential, thereby particularly focusing on Parkinson’s disease. Moreover, we use the acquired information to influence the differentiation of induced pluripotent stem cells towards defined neuronal fates.


Main publications

PUBLICATION

Zic-proteins are repressors of dopaminergic forebrain fate in mice and C. elegans.

Tiveron MC, Beclin C, Murgan S, Wild S, Angelova A, Marc J, Coré N, de Chevigny A, Herrera E, Bosio A, Bertrand V, Harold C.
J Neurosci. 2017 Sep 29. pii: 3888-16. PMID: 28972122

PUBLICATION

LAMP5 Fine-Tunes GABAergic Synaptic Transmission in Defined Circuits of the Mouse Brain.

Tiveron MC, Beurrier C, Céni C, Andriambao N, Combes A, Koehl M, Maurice N, Gatti E, Abrous DN, Kerkerian-Le Goff L, Pierre P, Cremer H.
PLoS One. 2016 Jun 7;11(6):e0157052. PMID: 27272053

PUBLICATION

Reducing Glypican-4 in ES Cells Improves Recovery in a Rat Model of Parkinson's Disease by Increasing the Production of Dopaminergic Neurons and Decreasing Teratoma Formation.

Fico A, de Chevigny A, Melon C, Bohic M, Kerkerian-Le Goff L, Maina F, Dono R, Cremer H.
J Neurosci. 2014 Jun 11;34(24):8318-23. PMID: 24920634

PUBLICATION

[Micro-RNA miR-7a controls the production of dopaminergic neurons in the mouse forebrain].

de Chevigny A, Cremer H, Coré N.
Med Sci (Paris). 2013 Feb;29(2):153-5. PMID: 23452602

PUBLICATION

Efficient neuronal in vitro and in vivo differentiation after immunomagnetic purification of mESC derived neuronal precursors.

Barral S, Ecklebe J, Tomiuk S, Tiveron MC, Desoeuvre A, Eckardt D, Cremer H, Bosio A.
Stem Cell Res. 2013 Mar;10(2):133-46. PMID: 23237958

PUBLICATION

Plexin-B2 regulates the proliferation and migration of neuroblasts in the postnatal and adult subventricular zone.

Saha B, Ypsilanti AR, Boutin C, Cremer H, Chédotal A.
J Neurosci. 2012 Nov 21;32(47):16892-905. PMID: 23175841

PUBLICATION

miR-7a regulation of Pax6 controls spatial origin of forebrain dopaminergic neurons.

de Chevigny A, Coré N, Follert P, Gaudin M, Barbry P, Béclin C, Cremer H.
Nat Neurosci. 2012 Jun 24;15(8):1120-6. PMID: 22729175

PUBLICATION

Agrin-signaling is necessary for the integration of newly generated neurons in the adult olfactory bulb.

Burk K, Desoeuvre A, Boutin C, Smith MA, Kröger S, Bosio A, Tiveron MC, Cremer H.
J Neurosci. 2012 Mar 14;32(11):3759-64. PMID: 22423096

PUBLICATION

Dynamic expression of the pro-dopaminergic transcription factors Pax6 and Dlx2 during postnatal olfactory bulb neurogenesis.

de Chevigny A, Core N, Follert P, Wild S, Bosio A, Yoshikawa K, Cremer H, Beclin C.
Front Cell Neurosci. 2012 Jan 5;6:6. PMID: 22371698

PUBLICATION

Targeted electroporation of defined lateral ventricular walls: a novel and rapid method to study fate specification during postnatal forebrain neurogenesis.

Fernández ME, Croce S, Boutin C, Cremer H, Raineteau O.
Neural Dev. 2011 Apr 5;6:13. PMID: 21466691

PUBLICATION

The SRC homology 2 domain protein Shep1 plays an important role in the penetration of olfactory sensory axons into the forebrain.

Wang L, Vervoort V, Wallez Y, Coré N, Cremer H, Pasquale EB.
J Neurosci. 2010 Sep 29;30(39):13201-10. PMID: 20881139

PUBLICATION

Expression and function of CXCR7 in the mouse forebrain.

Tiveron MC, Boutin C, Daou P, Moepps B, Cremer H.
J Neuroimmunol. 2010 Jun 5. PMID: 20965095

PUBLICATION

Coupling between hydrodynamic forces and planar cell polarity orients mammalian motile cilia.

Guirao B, Meunier A., Mortaud S, Aguilar A, Corsi JM., Strehl L, Hirota Y, Desoeuvre A, Boutin C, Han YG, Mirzadeh Z, Cremer H, Montcouquiol M, Sawamoto K, Spassky N.
Nat Cell Biol. 2010 Apr;12(4):341-50. PMID: 20305650

PUBLICATION

NeuroD1 induces terminal neuronal differentiation in olfactory neurogenesis.

Boutin C, Hardt O, de Chevigny A, Coré N, Goebbels S, Seidenfaden R, Bosio A, Cremer H.
Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):1201-6. PMID: 20080708

PUBLICATION

Gene expression analysis defines differences between region-specific GABAergic neurons.

Hardt O, Scholz C, Küsters D, Yanagawa Y, Pennartz S, Cremer H, Bosio A.
Mol Cell Neurosci. 2008 Nov;39(3):418-28. PMID: 18725299

PUBLICATION

CXCL12/CXCR4 signalling in neuronal cell migration.

Tiveron MC, Cremer H.
Curr Opin Neurobiol. 2008 Jun;18(3):237-44. PMID: 18644448

PUBLICATION

Efficient in vivo electroporation of the postnatal rodent forebrain.

Boutin C, Diestel S, Desoeuvre A, Tiveron MC, Cremer H.
PLoS One. 2008 Apr 2;3(4):e1883. PMID: 18382666

PUBLICATION

Molecular interaction between projection neuron precursors and invading interneurons via stromal-derived factor 1 (CXCL12)/CXCR4 signaling in the cortical subventricular zone/intermediate zone.

Tiveron MC, Rossel M, Moepps B, Zhang YL, Seidenfaden R, Favor J, König N, Cremer H.
J Neurosci. 2006 Dec 20;26(51):13273-8. PMID: 17182777

PUBLICATION

Glial conversion of SVZ-derived committed neuronal precursors after ectopic grafting into the adult brain.

Seidenfaden R, Desoeuvre A, Bosio A, Virard I, Cremer H.
Mol Cell Neurosci. 2006 May-Jun;32(1-2):187-98. PMID: 16730456

PUBLICATION

Dynamics of Cux2 expression suggests that an early pool of SVZ precursors is fated to become upper cortical layer neurons.

Zimmer C, Tiveron MC, Bodmer R, Cremer H.
Cereb Cortex. 2004 Dec;14(12):1408-20. PMID: 15238450

PUBLICATION

Purification of neuronal precursors from the adult mouse brain: comprehensive gene expression analysis provides new insights into the control of cell migration, differentiation, and homeostasis.

Pennartz S, Belvindrah R, Tomiuk S, Zimmer C, Hofmann K, Conradt M, Bosio A, Cremer H.
Mol Cell Neurosci. 2004 Apr;25(4):692-706. PMID: 15080897

PUBLICATION

Reelin is a detachment signal in tangential chain-migration during postnatal neurogenesis.

Hack I, Bancila M, Loulier K, Carroll P, Cremer H.
Nat Neurosci. 2002 Oct;5(10):939-45. PMID: 12244323
Other publications

Members more

    Alexandra Angelova Christophe Beclin   Ilona Chudotvorova Nathalie Coré-polo Jean-claude Platel Marie-catherine Tiveron Rousselin
Harold Cremer
Close window
Harold Cremer

Researcher

Close window
andrea Erni

Researcher

Close window
Clara Haubold

PhD student

  • 04 91 26 93 41
  • 1025
Alexandra Angelova
Close window
Alexandra Angelova

PhD student

Christophe Beclin
Close window
Christophe Beclin

Technical staff

Christophe Béclin is a specialist in small RNA function with a strong background in molecular biology. His main interest is the role of microRNAs in fate decisions and neuronal differentiation in the developing and adult brain.

Close window
Priscillia Bigotte

Trainee

Ilona Chudotvorova
Close window
Ilona Chudotvorova

Technical staff

Nathalie Coré-polo
Close window
Nathalie Coré-polo

Researcher

Nathalie Coré joined the group in 2008, bringing a strong background in developmental biology and mouse genetics. Her scientific interest focusses on the molecular cascades that regionalize neural stem cells in the forebrain.

Jean-claude Platel
Close window
Jean-claude Platel

Researcher

Jean-Claude is an INSERM scientist. He joined our Group after postdoctoral work at Yale University (with Angélique Bordey) and in Grenoble. JC is a specialist for in vivo imaging technologies and aims at understanding neural stem cell proliferation and synaptic integration in the adult brain.

Marie-catherine Tiveron Rousselin
Close window
Marie-catherine Tiveron Rousselin

Researcher

Marie-Catherine Tiveron is a founding member of the group. She is a specialist in neuroanatomy and mouse genetics, aiming at understanding the mechanisms underlying synaptic function of forebrain interneurons.

Alumni

Overview

Model organism
Biological process studied
  • Generation and integration of new neurons in the adult brain
Biological techniques
  • Cell transplantation
  • In vivo electroporation
  • Transgenic mice
  • Micrroarray
  • Deep sequencing
  • Cell sorting
Medical application
  • Parkinson’s disease
  • Neurodegenerative disease