The role of proneural genes in the generation of new neurons by adult hippocampal stem cells
Lead Research Organisation:
The Francis Crick Institute
Department Name: UNLISTED
Abstract
The role of proneural genes in the generation of new neurons by adult hippocampal stem cells
1) a) The Research Question
Neural stem cells located in the dentate gyrus, a subpart of the hippocampus, are essential for the production of new neurons in the hippocampus throughout life. Two genes that are known to influence the fate of cells toward a neuronal fate, Mash1 and Ngn2, are active in the cells that just joined the neuronal lineage and will soon become new neurons in the hippocampus. This makes them good candidates to play an important role in the production of new neurons in the adult hippocampus. However, the role of these two genes in this process is not known. In order to gain more insight about this, I will use several lines of genetically modified mice in order to permanently label and study the neurons that derive from cells in which Mash1 or Ngn2 were active. I will also use genetically modified mice to disrupt the function of Mash1 or Ngn2 in the adult hippocampus. These experiments will provide very insightful knowledge of the mechanisms leading to the production of new neurons in the adult hippocampus and the role played by Mash1 and Ngn2 in this process.
b) The scientific significance
i- Neural stem cells are present in the hippocampus and give rise to new neurons throughout life
For a long time, it was thought that no new neurons were generated in the brain once it reached adulthood. This explains why, when brain damages are suffered, the brain cannot properly heal. The brain can somewhat adapt and partially compensate for the injury, but the lost neurons are not properly replaced. However, the relatively recent discovery of neural stem cells started to shake up these views; in the right context, new neurons could be produced in the adult brain. This offers very promising perspectives for brain repair treatment.
It was recently shown that under normal circumstances, some discreet parts of the brain are producing new neurons throughout life. The hippocampus (more precisely the dentate gyrus) is one of them (van Praag et al., 2002; Kempermann et al., 2004). The hippocampus is a relatively well-studied part of the brain that is very important for learning and memory. More specifically, it is important for spatial learning, which is the faculty to learn the way around a new environment and to navigate properly in it. In addition to this, the hippocampus is also connected to the limbic system, which is the network dealing with emotions in the brain. The hippocampus itself is responsible for emotional learning; it helps us to determine what we like (the smell of chocolate) and helps us learns what we should be afraid of (the angry voice of your boss) and figure out how we should react to the situation (salivate or try to escape).
Production of new granule neurons occurs throughout life in the hippocampus, thanks to the presence of neural stem cells within it. Neural stem cells continue to divide, albeit slowly, in the adult brain, including in the hippocampus, to both maintaining the number of stem cells available and to produce new neurons or support cells. When a neural cell do divide, it gives rise to two daughter cells; one of them will be a neural stem cell, which assures the maintenance of the pool of stem cells in the brain. The other daughter cell will either become a support cell in the brain (glial cell) or a neuron. A group of neural stem cells can be found in the hippocampus, more precisely in the subgranular layer of the dentate gyrus. Throughout life, these neural stem cells can give rise to a support cells (oligodendrocytes or astrocytes), and/or to a neuron. In the hippocampus, the new neurons that are generated during adulthood are granule neurons. These neurons play an important role by relaying information to CA3 pyramidal neurons and other local interneurons within the hippocampus. Moreover, it was shown that the production of new granule
1) a) The Research Question
Neural stem cells located in the dentate gyrus, a subpart of the hippocampus, are essential for the production of new neurons in the hippocampus throughout life. Two genes that are known to influence the fate of cells toward a neuronal fate, Mash1 and Ngn2, are active in the cells that just joined the neuronal lineage and will soon become new neurons in the hippocampus. This makes them good candidates to play an important role in the production of new neurons in the adult hippocampus. However, the role of these two genes in this process is not known. In order to gain more insight about this, I will use several lines of genetically modified mice in order to permanently label and study the neurons that derive from cells in which Mash1 or Ngn2 were active. I will also use genetically modified mice to disrupt the function of Mash1 or Ngn2 in the adult hippocampus. These experiments will provide very insightful knowledge of the mechanisms leading to the production of new neurons in the adult hippocampus and the role played by Mash1 and Ngn2 in this process.
b) The scientific significance
i- Neural stem cells are present in the hippocampus and give rise to new neurons throughout life
For a long time, it was thought that no new neurons were generated in the brain once it reached adulthood. This explains why, when brain damages are suffered, the brain cannot properly heal. The brain can somewhat adapt and partially compensate for the injury, but the lost neurons are not properly replaced. However, the relatively recent discovery of neural stem cells started to shake up these views; in the right context, new neurons could be produced in the adult brain. This offers very promising perspectives for brain repair treatment.
It was recently shown that under normal circumstances, some discreet parts of the brain are producing new neurons throughout life. The hippocampus (more precisely the dentate gyrus) is one of them (van Praag et al., 2002; Kempermann et al., 2004). The hippocampus is a relatively well-studied part of the brain that is very important for learning and memory. More specifically, it is important for spatial learning, which is the faculty to learn the way around a new environment and to navigate properly in it. In addition to this, the hippocampus is also connected to the limbic system, which is the network dealing with emotions in the brain. The hippocampus itself is responsible for emotional learning; it helps us to determine what we like (the smell of chocolate) and helps us learns what we should be afraid of (the angry voice of your boss) and figure out how we should react to the situation (salivate or try to escape).
Production of new granule neurons occurs throughout life in the hippocampus, thanks to the presence of neural stem cells within it. Neural stem cells continue to divide, albeit slowly, in the adult brain, including in the hippocampus, to both maintaining the number of stem cells available and to produce new neurons or support cells. When a neural cell do divide, it gives rise to two daughter cells; one of them will be a neural stem cell, which assures the maintenance of the pool of stem cells in the brain. The other daughter cell will either become a support cell in the brain (glial cell) or a neuron. A group of neural stem cells can be found in the hippocampus, more precisely in the subgranular layer of the dentate gyrus. Throughout life, these neural stem cells can give rise to a support cells (oligodendrocytes or astrocytes), and/or to a neuron. In the hippocampus, the new neurons that are generated during adulthood are granule neurons. These neurons play an important role by relaying information to CA3 pyramidal neurons and other local interneurons within the hippocampus. Moreover, it was shown that the production of new granule
Technical Summary
Neural stem cells found in the subgranular zone of the dentate gyrus allow the generation of new granule neurons in the hippocampus throughout life. The generation of new granule neurons and their integration in the neuronal circuitry of the dentate gyrus is critical for long-term spatial memory and also for emotional memory. Disruption of adult neurogenesis in the hippocampus is linked to mood disorders such as anxiety and depression as well as neurodegenerative conditions such as Alzheimer's disease. The molecular mechanisms regulating neurogenesis in the adult hippocampus are poorly understood. Our laboratory recently showed that the proneural transcription factors Mash1 and Ngn2 are both involved in neurogenesis during embryogenesis and can promote neuronal fate in multipotent cells. However, their respective roles during adult neurogenesis have not been addressed. A genetic labelling approach (using newly generated, Mash1-CreERT2, Ngn2-CreERT2 inducible cre transgenic mouse lines) will be used to permanently label Mash1- and Ngn2-expressing progenitors and follow their long-term fate. This should confirm that these cells give rise to functional neurons that integrate into the neuronal circuitry of the dentate gyrus. The roles of Mash1 and Ngn2 during neurogenesis in the adult dentate gyrus will be assessed using conditional null alleles for Mash1 and Ngn2, the function of Mash1 or Ngn2 will be ablated, upon injection of tamoxifen, in the neural stem cells of the dentate gyrus. The effect of loss of function of either Mash1 or Ngn2 in the dentate gyrus will be assessed using different specific markers for granule neurons, astrocytes and oligodendrocytes. Given that new neurons are still formed in the mutant mice, their survival and integration into the hippocampal circuitry will be assessed using single-cell patch-clamp electrophysiology. Retrograde and anterograde, cre-inducible, markers will also be used to identify the neurons providing input signal to the new neurons and to identify the targets of these new granule neurons. This will provide important information about the integration of the newly born neurons into the dentate gyrus pre-existing neuronal circuitry. Together, these experiments will provide useful insights about the role of Mash1 and Ngn2 during adult neurogenesis, and provide greater knowledge for the design of future treatments for diseases arising from disrupted neurogenesis in the adult hippocampus.
Organisations
People |
ORCID iD |
| Melanie Lebel (Principal Investigator) |