Research opens up new possibilities for generating functional neurons in the adult brain from stem cells in conditions with of neuronal loss, such as neurodegenerative diseases.

Neurogenesis is a developmental process that generates new functional neurons and occurs throughout life in certain areas of the mammalian brain, such as the ventricular-subventricular zone (V-SVZ) lining the lateral ventricles and the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus.

Understanding how this neurogenesis occurs, what enhances or impairs it, could open the door not only to understanding certain neurodegenerative processes, but also to identifying new treatments that stimulate this “neuronal replacement” during life, thereby slowing age-associated cognitive degeneration or certain diseases.

New neurons produced in the adult SGZ integrate into the adjacent cell layers and participate in learning and memory. In addition, several physiological and pathological situations, such as physical exercise, task learning, and environmental stimuli, can stimulate neurogenesis in the adult DG (see HERE).

The adult SGZ neurogenic niche is maintained through the activation of radial glia-like (RGL) neural stem cells (NSC). They are mostly in a reversible state of quiescence (resting) that protects cells from DNA damage and prevents depletion of the RGL population.

Under certain circumstances, a relatively small population of quiescent RGLs (qRGLs) will activate and will divide symmetrically to self-renew, or divide asymmetrically to generate an RGL and an intermediate progenitor cell (IPC). The IPCs generate neuroblasts, which exit the cell cycle to differentiate into granule neurons (GNs).

These new findings are very promising to try to understand how neurogenesis is maintained in adults, attempting to demonstrate the mechanisms that control the balance between quiescence and activation in the RGL population.

The present study (Cell Reports) shows that the transcription factors Sox5 and Sox6 of the SoxD gene are necessary for neural stem cell activation and for the generation of new neurons in the adult hippocampus in mice. In that context, the study also shows that Sox5 and Sox6 modulate the transcription of the stem cell activator Ascl1.

The ability to generate new neurons in the adult hippocampus, which is responsible for managing long-term memory, depends on the activation of reversibly quiescent NSC with RGL morphology. This paper shows that the genetic expression of SoxD transcription factors Sox5 and Sox6 is enriched in activated RGLs. Using inducible deletion of Sox5 or Sox6 in the adult mouse brain, the authors show that both genes are necessary for RGL activation and the generation of new neurons.

In contrast, Sox5 overexpression in cultured NSCs interferes with their entry in quiescence. Expression of the proneural protein Ascl1 (a key RGL regulator) is severely downregulated in SoxD-deficient RGLs.

 

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