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NRF2: An emerging role in neural stem cell regulation and neurogenesis

Research output: Contribution to journalReview articlepeer-review

Original languageEnglish
Pages (from-to)437-446
Number of pages10
JournalFree radical biology & medicine
Volume193
Early online date3 Nov 2022
DOIs
Accepted/In press17 Oct 2022
E-pub ahead of print3 Nov 2022
Published20 Nov 2022

Bibliographical note

Funding Information: Marking the earliest stage of embryonic neurogenesis is the local accumulation of symmetrically dividing neuroectodermal cells which consequently expand the layer and form a tube-like structure termed the neural tube at around E8.5-10 [13]. With expansion, a group of neuroectodermal cells are enclosed within the neural tube (also referred to as neuroepithelial cells) and they begin to radially stretch. In doing so, they transform into another distinct NSC subtype morphologically and genetically reminiscent of astrocytes: the radial glial cell (RG). Through successive divisions, RGs populate the developing brain with neural progeny of nearly every kind in a temporally and spatially coordinated manner. The rich diversity of progeny generated in the CNS arises from the various types of symmetric and asymmetric divisions of progenitor cells [14,15]. From around E12.5 in mice, an asymmetrically dividing RG exclusively supports neurogenesis either by directly producing a daughter neuron or neuronally-restricted intermediate progenitor cell n (IPC) [16]. nIPCs then go on to exhibit symmetric division resulting in the gain of another nIPC or alternatively undergoes terminal symmetric division where the nIPC spawns a terminally differentiating daughter neuron and subsequently exits the cell cycle itself to become another neuron [16]. Over the course of neuronal differentiation, a major remodelling of cytoskeletal architecture and composition occurs which reshape the morphology of the immature neuron [17]. Newly derived neurons then migrate distally along parental RG radial processes that span the neuroectodermal layers. During late embryogenesis at around E18 in mice, RGs asymmetrically divide generating oligodendrocyte-restricted IPCs or otherwise convert into astrocytes [18] (Fig. 2).Aside from adult NSC maintenance, NRF2 may also support neuronal lineage specification and maturation within the hippocampus. In the absence of NRF2, the balance between neuronal and glial lineage-specification is offset where, coinciding with a loss of neurons, astrocyte numbers increased by almost half [58]. Meanwhile, the prevailing neuronal population displays an underdeveloped phenotype marked by a loss of branching complexity [58]. Perhaps culminating from all the aberrations described here, authors also found electrical stimulation of fibres projecting into and supplying the DG generated much weaker excitatory post synaptic potentials from granule cells of NRF2-null mice than wildtype [58]. As a function normally reliant upon the integrity of the SGZ, this outcome indicates a deterioration in hippocampal neurogenesis with potential consequences for the cognitive faculties it underpins.This research was supported by grants from the Medical Research Council, UK (E.B. P.Z. G.E.M.) and Stavanger University Hospital, Norway (R.K. D.A.). G.E.M. further acknowledges support of the European COST Action CA20121: Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases (BenBedPhar, https://benbedphar.org/about-benbedphar). Funding Information: This research was supported by grants from the Medical Research Council , UK (E.B., P.Z., G.E.M.) and Stavanger University Hospital, Norway (R.K., D.A.). G.E.M. further acknowledges support of the European COST Action CA20121 : Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases (BenBedPhar, https://benbedphar.org/about-benbedphar ). Publisher Copyright: © 2022

King's Authors

Abstract

The birth of new neurons from neural stem cells (NSC)s during developmental and adult neurogenesis arises from a myriad of highly complex signalling cascades. Emerging as one of these is the nuclear factor erythroid 2-related factor (NRF2)-signaling pathway. Regulation by NRF2 is reported to span the neurogenic process from early neural lineage specification and NSC regulation to neuronal fate commitment and differentiation. Here, we review these reports selecting only those where NRF2 signaling was directly manipulated to provide a clearer case for a direct role of NRF2 in embryonic and adult neurogenesis. With few studies providing mechanistic insight into this relationship, we lastly discuss key pathways linking NRF2 and stem cell regulation outside the neural lineage to shed light on mechanisms that may also be relevant to NSCs and neurogenesis.

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