Retinoic acid (RA) is the active ingredient of vitamin A. It exerts its canonical activity by binding to nuclear RA receptors (RARs) to regulate gene expression. Increasingly, RA is also known to elicit nongenomic RAR-independent activities, most widely detected in activating extracellular regulated kinase (ERK)1/2. This study validated the functional role of cellular retinoic acid-binding protein 1 (Crabp1) in mediating nongenomic activity in RA, specifically activating ERK1/2 to rapidly augment the cell cycle by expanding the growth 1 phase and slowing down embryonic stem cell and neural stem cell (NSC) proliferation. The study further uncovered the physiological activity of Crabp1 in modulating NSC proliferation and animal behavior. In the Crabp1 knockout mouse hippocampus, where Crabp1 is otherwise detected in the subgranular zone, neurogenesis and NSC proliferation increased and hippocampus-dependent brain functions such as learning and memory correspondingly improved. This study established the physiological role of Crabp1 in modulating stem cell proliferation and hippocampus-dependent brain activities such as learning and memory.
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the growth 1 (G1) phase by chemical inhibition of cyclin-dependent kinase (CDK) 2−cyclin E or by RNA interference–mediated silencing of CDK4−cyclin D results in increased neurogenesis (18). In animals, there are substantial stem cell populations mostly in the brain, especially the hippocampus. NSCs reside in the subgranular zone (SGZ) of the hippocampus and in the subventricular zone (19). Importantly during NSC proliferation and differentiation into neurons and astrocytes, the intracellular Raf-ERK1/2 signaling pathway is activated (20). In adults, hippocampal neurogenesis is important for maintaining hippocampal plasticity and cognitive function. New neurons matured from NSCs incorporate into the SGZ of the dentate gyrus to support hippocampus-dependent activities such as learning and memory (21, 22). These new neurons heighten CA3 synaptic plasticity. Maintenance of the NSC pool has been strongly linked to the plastic potential and function of the brain (21). This is supported by the finding that optogenetic silencing of 4-week-old neurons impaired spatial and contextual memory retrieval (23).
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