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.
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.
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.
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.
July 11th, 2019
Neuronal integration in the adult mouse olfactory bulb is a non-selective addition process.
September 29th, 2017
Zic-proteins are repressors of dopaminergic forebrain fate in mice and C. elegans.
June 7th, 2016
LAMP5 Fine-Tunes GABAergic Synaptic Transmission in Defined Circuits of the Mouse Brain.
June 17th, 2014
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.
February 28th, 2013
[Micro-RNA miR-7a controls the production of dopaminergic neurons in the mouse forebrain].
February 13th, 2013
Efficient neuronal in vitro and in vivo differentiation after immunomagnetic purification of mESC derived neuronal precursors.
November 21st, 2012
Plexin-B2 regulates the proliferation and migration of neuroblasts in the postnatal and adult subventricular zone.
June 24th, 2012
miR-7a regulation of Pax6 controls spatial origin of forebrain dopaminergic neurons.
March 14th, 2012
Agrin-signaling is necessary for the integration of newly generated neurons in the adult olfactory bulb.
January 5th, 2012
Dynamic expression of the pro-dopaminergic transcription factors Pax6 and Dlx2 during postnatal olfactory bulb neurogenesis.
April 13th, 2011
Targeted electroporation of defined lateral ventricular walls: a novel and rapid method to study fate specification during postnatal forebrain neurogenesis.
September 29th, 2010
The SRC homology 2 domain protein Shep1 plays an important role in the penetration of olfactory sensory axons into the forebrain.
June 5th, 2010
Expression and function of CXCR7 in the mouse forebrain.
April 1st, 2010
Coupling between hydrodynamic forces and planar cell polarity orients mammalian motile cilia.
January 19th, 2010
NeuroD1 induces terminal neuronal differentiation in olfactory neurogenesis.
November 1st, 2008
Gene expression analysis defines differences between region-specific GABAergic neurons.
June 1st, 2008
CXCL12/CXCR4 signalling in neuronal cell migration.
April 2nd, 2008
Efficient in vivo electroporation of the postnatal rodent forebrain.
December 20th, 2006
Molecular interaction between projection neuron precursors and invading interneurons via stromal-derived factor 1 (CXCL12)/CXCR4 signaling in the cortical subventricular zone/intermediate zone.
May 1st, 2006
Glial conversion of SVZ-derived committed neuronal precursors after ectopic grafting into the adult brain.
December 1st, 2004
Dynamics of Cux2 expression suggests that an early pool of SVZ precursors is fated to become upper cortical layer neurons.
April 1st, 2004
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.
October 1st, 2002