Cell-intrinsic signals that regulate adult neurogenesis in vivo: insights from inducible approaches

Abstract

The process by which adult neural stem cells generate new and functionally integrated neurons in the adult mammalian brain has been intensely studied, but much more remains to be discovered. It is known that neural progenitors progress through distinct stages to become mature neurons, and this progression is tightly controlled by cell-cell interactions and signals in the neurogenic niche. However, less is known about the cell-intrinsic signaling required for proper progression through stages of adult neurogenesis. Techniques have recently been developed to manipulate genes specifically in adult neural stem cells and progenitors in vivo, such as the use of inducible transgenic mice and viral-mediated gene transduction. A critical mass of publications utilizing these techniques has been reached, making it timely to review which molecules are now known to play a cell-intrinsic role in regulating adult neurogenesis in vivo. By drawing attention to these isolated molecules (e.g. Notch), we hope to stimulate a broad effort to understand the complex and compelling cascades of intrinsic signaling molecules important to adult neurogenesis. Understanding this process opens the possibility of understanding brain functions subserved by neurogenesis, such as memory, and also of harnessing neural stem cells for repair of the diseased and injured brain.

Figure 1. Adult neurogenesis occurs primarily in the subventricular zone (SVZ) and subgranular zone (SVZ)

A sagittal view of the adult mouse brain, the neurogenic regions are indicated in blue. In the SVZ, stem cells (green) reside in the wall of the lateral ventricle, just below the ependymal layer (gray), and give rise to neural progenitors (blue) and neuroblasts (purple). These neuroblasts migrate in chains along the rostral migratory stream (RMS) to reach the olfocatory bulb (OB), where they mature into functionally integrated neurons. In the SGZ of the hippocampal dentate gyrus (DG), stem cells (green) clustered near the base of the hippocampal DG granule cell layer (GCL) give rise to progenitors (light blue). These eventually give rise to immature (magenta) and mature (peach) granule cell neurons that primarily exist in the inner or hilar-half of the GCL but extend their processes out to the molecular layer to receive cortical input. Note that SVZ progenitors and their progeny migrate a relatively long distance to the OB to give rise to mature neurons, while SGZ progenitors move barely into the GCL to give rise to mature neurons.

Figure 2. Adult neurogenesis is a process with distinct stages

The process of adult neurogenesis – stem cells on the left giving rise to rapidly dividing progenitors, which in turn develop into immature and eventually mature neurons on the right – is shown in schematic form in both the hippocampal SGZ (top row) and SVZ (bottom row). In both the SVZ and SGZ, stem cells express the markers GLAST, Nestin, and GFAP (see green band across the bottom). Stem cells in both the SGZ and SVZ divide infrequently to self-renew and give rise to transit amplifying progenitors. SGZ: Self-renewal in the SGZ is dependent on Notch signaling. Transit amplifying progenitors give rise to lineage-restricted neuroblasts, both of which proliferate to expand their population. Several pathways converge to promote proliferation of these populations in the SGZ. Notch and DISC1 promote basal proliferation, while TrkB promotes proliferation in response to antidepressants (AD). DISC1 may promote proliferation by inhibiting GSK3beta and cell cycle exit. Notch signaling also negatively regulates cell cycle exit. Overexpression of Ascl1 in SGZ progenitors leads to a change in fate from neuronal to oligodendrocyte. This is specific to the SGZ. Once SGZ neuroblasts exit the cell cycle, they differentiate into neurons and extend dendrites. Maturation and survival of newborn neurons is positively regulated by many pathways, including Cdk5, NMDAR, TrkB, and Notch, while DISC1 negatively regulates maturation. SVZ: Intrinsic regulation of SVZ neurogenesis is less clear, but it is known that Notch signaling maintains ependymal cells in a differentiated state. Without Notch, these cells can contribute to SVZ neurogenesis. Smad4, a downstream target of BMP signaling, is required to inhibit oligodendrocyte differentiation of SVZ progenitors. The colored bands on the very bottom of the schematic illustrate the distinct, but overlapping, stages of neurogenesis in both the SGZ and SVZ that are transfected by lentivirus and retrovirus.

Figure 3. Potential convergence of cell-intrinsic signaling pathways for the regulation of adult neurogenesis

This schematic of a single cell (with its bilipid membrane, cytoplasm, and nucleus containing DNA and transcriptional elements) proposes a hypothesis of how many of the individual cell-intrinsic components discussed in this review may act in concert or in opposition to regulate stages of adult neurogenesis. Components summarized in this review are indicated in yellow. Direct signaling is indicated by solid lines, while indirect signaling is indicated by dashed lines. Note that several of these proteins receive signals from outside the cell and from the neurogenic niche to regulate differentiation, proliferation, survival, and maturation.