Role of all-trans retinoic acid in neurite outgrowth and axonal elongation.

The vitamin A metabolite, all-trans retinoic acid (atRA) plays essential roles in nervous system development, including neuronal patterning, survival, and neurite outgrowth. Our understanding of how the vitamin A acid functions in neurite outgrowth comes largely from cultured embryonic neurons and model neuronal cell systems including human neuroblastoma cells. Specifically, atRA has been shown to increase neurite outgrowth from embryonic DRG, sympathetic, spinal cord, and olfactory receptor neurons, as well as dissociated cerebra and retina explants. A role for atRA in axonal elongation is also supported by a limited number of studies in vivo, in which a deficiency in retinoid signaling produced either by dietary or genetic means has been shown to alter neurite outgrowth from the spinal cord and hindbrain regions. Human neuroblastoma cells also show enhanced numbers of neurites and longer processes in response to atRA. The mechanism whereby retinoids regulate neurite outgrowth includes, but is not limited to, the regulation of the transcription of neurotrophin receptors. More recent evidence supports a role for atRA in regulating components of other signaling pathways or candidate neurite-regulating factors. Some of these effects, such as that on neuron navigator 2 (NAV2), may be direct, whereas others may be secondary to other atRA-induced changes in the cell. This review focuses on what is currently known about neurite initiation and growth, with emphasis on the manner in which atRA may influence these events.