TEAM

Molecular control of neurogenesis

Group leader : H. Cremer

We study the genes and molecular mechanisms that control determination and proliferation of neural stem cells and their differentiation into functional neurons.

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.

In the process of brain development over 1000 different types of neurons are generated from initially homogeneous stem cell population.
At which level this diversity is encoded? How is the proliferation of stem cells controlled to generate the correct number of neurons? What happens when proliferation control goes wrong and brain cancer develops? How do neurons integrate into the circuitry and what is their specific function?

We use the ongoing neurogenesis that occurs in the postnatal mammalian brain to address these questions and identify the signals and molecular cascades that control specific steps in neuron production. A particular focus of our work is set on the role of RNAs that do not encode proteins, but have regulatory functions to provide the stability and flexibility that is needed to generate and maintain a functional brain.

FOR SPECIALISTS

In mammals, including humans, neurogenesis is not limited to embryonic stages but is maintained in specific regions of the postnatal and adult brain. For example, in the forebrain neural stem cells along the ventricles keep generating throughout life new neuronal precursors that migrate into the olfactory bulb where they are added to the circuitry as interneurons that use GABA, dopamine and glutamate as their neurotransmitters. This process, resembling ongoing neural development, presents all crucial steps that are also seen in the embryo. However, as the process occurs ex-utero it is highly amenable to experimental manipulation, like in vivo electroporation, lineage tracing, and manipulation by chemo- and optogenetics. In addition, consequences of these changes can be easily observed by classical microscopy or by multi-photon in vivo microscopy.

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)

In our lab we use this experimental model to investigate how neuron production and integration are controlled at the molecular and physiological levels, both in the normal and the diseased brain.

Specifically, we ask: 

How is the stem cell compartment regionalized to produce different types of neurons? What are the mechanisms that generate this diversity in first place and maintain it throughout the animal’s life? 

We found that cross regulatory interactions between transcription factors underlie this diversity and use new technologies to provide insight into their expression and function.

What is the role of non-coding RNAs in the process of neurogenesis?

We found that stem cell regionalization and proliferation is fine-tuned in an interplay between microRNAs and long non-coding RNAs. We develop new tools and strategies to investigate these interactions in the living brain.

What happens when proliferation and differentiation of new neurons gets out of control and cancer develops? What is the function of non-coding RNAs in cancer induction and progression? 

To address this question, we study the role of different signaling pathways in the development of glioma and use innovative experimental strategies to identify the precise role of microRNAs in cancer.

How are new neurons are integrated in the postnatal and adult brain and how they achieve their specific function?

Using in vivo multiphoton imaging we found that olfactory bulb neurogenesis is not a replacement process, as has been thought so far, but that new neurons are constantly added to the structure, leading to significant growths. We investigate the role of this “ongoing development” and analyze the contribution of the different neuronal subtypes to odor perception and computing.


Selected publications

PUBLICATION

Stem cell regionalization during olfactory bulb neurogenesis depends on regulatory interactions between Vax1 and Pax6

Nathalie Coré, Andrea Erni, Hanne M Hoffmann, Pamela L Mellon, Andrew J Saurin, Christophe Beclin, Harold Cremer
Elife . 2020 Aug 7;9:e58215. doi: 10.7554/eLife.58215. PMID: 32762844

PUBLICATION

Neuronal integration in the adult mouse olfactory bulb is a non-selective addition process.

Platel JC, Angelova A, Bugeon S, Wallace J, Ganay T, Chudotvorova I, Deloulme JC, Béclin C, Tiveron MC, Coré N, Murthy VN, Cremer H.
Elife. 2019 Jul 11;8. pii: e44830. doi: 10.7554/eLife.44830. PMID: 31294694

PUBLICATION

Direct and efficient transfection of mouse neural stem cells and mature neurons by in vivo mRNA electroporation

Stéphane Bugeon, Antoine de Chevigny, Camille Boutin, Nathalie Coré, Stefan Wild, Andreas Bosio, Harold Cremer, Christophe Beclin
Development 2017 144: 3968-3977; doi: 10.1242/dev.151381 PMID: 28982684

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

miR-200 family controls late steps of postnatal forebrain neurogenesis via Zeb2 inhibition

Christophe Beclin, Philipp Follert, Elke Stappers, Serena Barral, Nathalie Coré, Antoine de Chevigny, Virginie Magnone, Kévin Lebrigand, Ute Bissels, Danny Huylebroeck, Andreas Bosio, Pascal Barbry, Eve Seuntjens, Harold Cremer
Sci Rep . 2016 Oct 21;6:35729. doi: 10.1038/srep35729. PMID: 27767083

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

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

Antoine de Chevigny, Nathalie Coré, Philipp Follert, Marion Gaudin, Pascal Barbry, Christophe Béclin, Harold Cremer
Nat Neurosci . 2012 Jun 24;15(8):1120-6. doi: 10.1038/nn.3142. PMID: 22729175

PUBLICATION

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

Katja Burk, Angelique Desoeuvre, Camille Boutin, Martin A Smith, Stephan Kröger, Andreas Bosio, Marie-Catherine Tiveron, Harold Cremer
J Neurosci . 2012 Mar 14;32(11):3759-64. PMID: 22423096

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

[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

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

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

Interactions

IBDM
NATIONAL
INTERNATIONAL
  • Annalisa Fico, Institute of Genetics and Biophysics (IGB), Naples, Italy
  • Gunther Meister, University of Regensburg, Germany
  • Andreas Bosio, Miltenyi Biotec, Bergisch Gladbach Germany
  • Chiara Bardella, University of Birmingham, UK

Funding

FRM funding for H. Cremer Team from IBDM, IBDML

ANR funding for H. Cremer Team from IBDM, IBDML

FRC funding for H. Cremer Team from IBDM, IBDML

FRM

Members more

  Christophe Beclin Melanie Comet Nathalie Coré-polo Andrea Erni Mathieu Loizeau Jean-claude Platel Marie-catherine Tiveron Rousselin
Harold Cremer
Close window
Harold Cremer

Researcher

Close window
Maria isabel Ardaya

Visiting Scientist

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.

Melanie Comet
Close window
Melanie Comet

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.

Andrea Erni
Close window
Andrea Erni

Postdoctoral fellow

Mathieu Loizeau
Close window
Mathieu Loizeau

PhD student

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
  • Neurogenesis
  • Neuronal function
Biological techniques
  • Transgenesis
  • In vivo brain electroporation
Medical application
  • Cell therapy
  • Parkinson’s disease
  • Brain cancer
  • Glioblastoma