Neurogenesis is a vital process whereby new neurons are synthesized from neural stem cells. It is an essential step in the developing embryo, helping to form the fetal brain.
Neurons in the brain. Image Credit: MP Art/Shutterstock.com
More recently, it has also been discovered to be a fundamental mechanism in the adult brain, particularly in the hippocampus (an area of the brain involved in memory and spatial navigation) and the amygdala (responsible for the processing of emotions). Here, we discuss the cell biology underlying this crucial function.
Neural stem cells of the mammalian central nervous system (CNS) are responsible for generating the full array of neural cell types. In addition, they produce astrocytes and oligodendrocytes, types of macroglial cells that are implicated in maintaining the structural integrity of cerebral tissue. Growing evidence is also linking the malfunctioning of these cells to an array of neurological diseases, such as Parkinson’s.
The process of neurogenesis relies on both symmetric cell divisions of neural stem cells, where two identical daughter cells are produced, as well as asymmetric cell divisions, where one daughter cell identical to the mother is produced and a second, different cell type is generated.
Neurogenesis occurs in slightly different ways in the embryonic brain and the adult brain. In embryonic neurogenesis, the ventricular zone (VZ) serves as the primary location for this process, and the sub-ventricular zone (SVZ), which sits superficial to the VZ, is considered to be the secondary proliferative zone and is active during the later stages of neuronal production.
Embryonic neurogenesis begins with the differentiation of neuroepithelial cells into radial glia (RG). These cells begin life in the neural tube, arising from the ectoderm during the expansion of the tube. RG cells can be recognized by their expression of certain antigens (GLAST, BLBP, and GFAP). They can also be identified through their radial alignment and bipolar morphology.
Studies have demonstrated that in embryonic neurogenesis, neuroepithelial cells first go through a stage of self-renewing symmetric divisions that result in the growth of the precursor cell pool. This happens at the early stages of embryonic development and helps to form the neural plate. Once the neural tube has closed, the activity of the neuroepithelial cells changes and the cells begin up-regulating glial-specific factors, at this point, they convert into RG cells and are capable of generating neurons.
Initially, these RG cells proliferate the VZ via symmetric division. However, the cells switch to asymmetric divisions at the onset of cortical neurogenesis, producing one identical self-renewed RG cell and one daughter neuronal cell. This process indirectly adds vast numbers of neuronal daughter cells into the cortex by producing neural precursor daughter cells that migrate to the SVZ where they go through symmetric division to produce pairs of daughter neurons.
Neurogenesis in the adult brain
While it is well established that embryonic neurogenesis takes place in two distinct neural regions, the VZ and the SVZ, studies have shown that neurogenesis in the adult brain also occurs within the external granular layer (EGL) of the cerebellum. Precursor cells derived from the prenatal brain are located within these proliferative zones and are implicated in neurogenesis in the adult brain.
The adult debate gyrus is occupied by neuroepithelial cells that share similarities with RG cells. Because they overlap fundamental properties, these cells are often referred to as RG-like (RGL) cells. They are also known as Type 1 cells. The subgranular zone (SGZ) of the dentate gyrus is home to these type 1 cells which have complex radial extensions that permeate the granule cell layer into the molecular layer where their axon terminals meet with synapses and vasculature. Type 1 cells have been shown to generate adult granule neurons and can be highly proliferative. Studies have shown type 1 cells can divide both symmetrically and asymmetrically during mitosis.
During the process of neurogenic division, type 1 cells produce intermediate progenitor (IP) cells known as type 2 cells. Type 2 cells express T-brain gene-2 (Tbr2) and produce neuronal cells via limited rounds of mitotic divisions. The new daughter cells generated by type 2 cells migrate radially to the granular cell layer. Here, they transform into Prox1+ debate granule neurons.
The adult brain harbors neural stem cells in a dormant state where they can remain for long periods. Once triggered, these dormant cells become active and begin the process of self-renewal, initiating divisions and the generation of new cells that can differentiate into neurons. For these new neurons to be fully realized, these neural stem cells must undergo the numerous stages of adult neurogenesis including activation, migration, and finally, integration into the brain’s existing neural circuitry.
Our understanding of adult neurogenesis is still evolving. Recent evidence has revealed that neural stem cells can migrate long distances in instances where the brain is injured, suggesting that adult neurogenesis may play a vital role in the healing process. Additionally, its activity within the hippocampus and amygdala suggests its role in memory, spatial navigation, and emotion processing. Further research will undoubtedly continue to grow our understanding of the function of neurogenesis in the adult brain.
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- Obernier, K., Cebrian-Silla, A., Thomson, M., Parraguez, J., Anderson, R., Guinto, C., Rodas Rodriguez, J., Garcia-Verdugo, J. and Alvarez-Buylla, A., 2018. Adult Neurogenesis Is Sustained by Symmetric Self-Renewal and Differentiation. Cell Stem Cell, 22(2), pp.221-234.e8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802882/
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