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

Abstract

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.

Mammalian Glycerophosphodiester Phosphodiesterases

“…26,27) On the other hand, retinoic acid (RA), an active metabolite of vitamin A, is known to play important roles in nervous system development, including neuronal differentiation, patterning, and outgrowth. 28) In particular, RA is known to induce neurite outgrowth from the spinal cord, dorsal root ganglia neurons, and neuroblastoma cells. [29][30][31] Previous reports have demonstrated that one mechanism whereby RA regulates neuronal outgrowth is by modulation of the expression of neurotrophin receptors, including TrkA and p75 NTR , 30,32) but our understanding of the mechanisms involved in the control of neuronal differentiation and outgrowth by RA remains limited.…”

Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells

“…[12][13][14] In addition, retinoids can also downregulate the expression of certain genes such as N-MYC, concurrent with the arrest of cell proliferation. 11,5,16 Elucidating the mechanisms behind the differentiation of neuroblastoma cells is therefore of clinical importance.…”

Retinoic acid downregulates Rae1 leading to APCCdh1 activation and neuroblastoma SH-SY5Y differentiation

“…Thus, retinoic acid downregulates Rae1, hence facilitating APC Cdh1 -mediated Skp2 degradation leading to the arrest of cell cycle progression and neuroblastoma differentiation. Oncogene (2008) 27, 3339-3344;doi:10.1038/sj.onc.1210987;published online 21 January 2008 Keywords: retinoic acid; Rae1; Cdh1; Skp2; p27; neuroblastoma It is well established that the vitamin A metabolite, all-trans-retinoic acid (RA) plays important roles in the development of the mammalian nervous system, including neural patterning and development of cerebral structure (Maden, 2002;Clagett-Dame et al, 2006). In certain neural progenitor niches of the postnatal brain, RA downregulates cellular proliferation and promotes neurogenesis (Matthay, 1999), an observation that has raised the interest of RA in neurorepair strategies for some human neuroblastomas (Reynolds et al, 2003).…”