Transcriptional regulation of adult neural stem/progenitor cells: tales from the subventricular zone

Abstract

In rodents, well characterized neurogenic niches of the adult brain, such as the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampus, support the maintenance of neural/stem progenitor cells (NSPCs) and the production of new neurons throughout the lifespan. The adult neurogenic process is dependent on the intrinsic gene expression signatures of NSPCs that make them competent for self-renewal and neuronal differentiation. At the same time, it is receptive to regulation by various extracellular signals that allow the modulation of neuronal production and integration into brain circuitries by various physiological stimuli. A drawback of this plasticity is the sensitivity of adult neurogenesis to alterations of the niche environment that can occur due to aging, injury or disease. At the core of the molecular mechanisms regulating neurogenesis, several transcription factors have been identified that maintain NSPC identity and mediate NSPC response to extrinsic cues. Here, we focus on REST, Egr1 and Dbx2 and their roles in adult neurogenesis, especially in the subventricular zone. We review recent work from our and other laboratories implicating these transcription factors in the control of NSPC proliferation and differentiation and in the response of NSPCs to extrinsic influences from the niche. We also discuss how their altered regulation may affect the neurogenic process in the aged and in the diseased brain. Finally, we highlight key open questions that need to be addressed to foster our understanding of the transcriptional mechanisms controlling adult neurogenesis.

Keywords: adult neurogenesis; aging; extracellular signaling; gene regulation; neural stem/progenitor cells; transcription factors.

Figure 1

Proposed model of the REST-dependent control of NSPC proliferation and neuron differentiation/survival. Decreased levels of REST activity in NSPCs derepress the transcription of genes associated with the inhibition of NSPC proliferation and the stimulation of differentiation, thus promoting NSPC progression along the neurogenic lineage. In differentiated neurons, REST levels and/or cellular localization change as a result of different physiological or pathological events. These alterations of REST activity may exert neurotoxic or neuroprotective effects, with context-dependent mechanisms. NSPCs: Neural stem/progenitor cells; REST: repressor element 1-silencing transcription factor.

Figure 2

Proposed model of the regulation of SVZ NSPC proliferation by the antagonistic activities of Dbx2 and Egr1. EGFR signaling may promote NSPC proliferation by repressing Dbx2 and by activating Egr1 expression. In turn, these TFs may exert opposite effects on the expression of genes coding for cell cycle activators and inhibitors and for other regulators of NSPC proliferation. According to this model, changes in the levels of EGFR signaling may be instrumental, acting via Dbx2 and Egr1, to the decrease in NSPC proliferation associated with the transition towards quiescent or differentiating states or with aging. EGFR: Epidermal growth factor receptor; NSPCs: neural stem/progenitor cells; SVZ: subventricular zone; TFs: transcription factors.