Retinoic acid receptor β2 and neurite outgrowth in the adult mouse spinal cord in vitro

Abstract

Retinoic acid, acting through the nuclear retinoic acid receptor β2(RARβ2), stimulates neurite outgrowth from peripheral nervous system tissue that has the capacity to regenerate neurites, namely, embryonic and adult dorsal root ganglia. Similarly, in central nervous system tissue that can regenerate, namely, embryonic mouse spinal cord, retinoic acid also stimulates neurite outgrowth and RARβ2 is upregulated. By contrast, in the adult mouse spinal cord, which cannot regenerate, no such upregulation of RARβ2 by retinoic acid is observed and no neurites are extended in vitro. To test our hypothesis that the upregulation of RARβ2 is crucial to neurite regeneration, we have transduced adult mouse or rat spinal cord in vitro with a minimal equine infectious anaemia virus vector expressing RARβ2. After transduction, prolific neurite outgrowth occurs. Outgrowth does not occur when the cord is transduced with a different isoform of RARβ nor does it occur following treatment with nerve growth factor. These data demonstrate that RARβ2 is involved in neurite outgrowth, at least in vitro, and that this gene may in the future be of some therapeutic use.

Rapid Effects of Retinoic Acid on CREB and ERK Phosphorylation in Neuronal Cells

“…Dorsal root ganglia cells express different isoforms of RA receptors (Corcoran and Maden, 1999;Corcoran et al, 2002) and respond to the retinoid by extending neurites (Corcoran et al, 2000). Furthermore, we have observed that the cerebrocortical cell cultures undergo important morphological changes upon incubation with RA (unpublished observations).…”

“…The high levels of RAR␤ could play an important role in the phenotypic changes induced by the retinoid, because this receptor is thought to be responsible for RA-mediated differentiation of several cell types (Liu et al, 1996;Faria et al, 1999;Pérez-Juste and Aranda, 1999). Moreover, it has been postulated that RAR␤ induction is an essential part of the neuronal differentiation process induced by NGF in neuronal cells (Corcoran and Maden, 1999;Corcoran et al, 2002).…”

“…The high levels of RAR␤ could play an important role in the phenotypic changes induced by the retinoid, because this receptor is thought to be responsible for RA-mediated differentiation of several cell types (Liu et al, 1996;Faria et al, 1999;Pérez-Juste and Aranda, 1999). Moreover, it has been postulated that RAR␤ induction is an essential part of the neuronal differentiation process induced by NGF in neuronal cells (Corcoran and Maden, 1999;Corcoran et al, 2002).In this work we demonstrate that RA induces CREB phosphorylation and CREB-mediated transcription in the PC12 cell clones that undergo morphological differentiation upon incubation with the retinoid. The effects of RA are similar to those caused by NGF and the combination of both factors does not induce further changes, suggesting that they could use common pathways to stimulate CREB phosphorylation.…”

Induction of corticospinal regeneration by lentiviral trkB-induced Erk activation

“…Although others have used viral transduction of trkB to mediate cell survival, a process largely dependent on Akt signaling (24), we predicted that overexpression of trkB would confer the ability to regenerate on refractory adult corticospinal axons, and that this growth would depend on canonical signaling through Erk/Map kinase pathways classically associated with neurite outgrowth during development. Previous studies have adopted analogous approaches by overexpressing ␣-integrins or retinoic receptor-␤2, in either in vitro or dorsal root injury paradigms (25)(26)(27). However, these studies (25)(26)(27) utilized cell systems in which regeneration had been achieved previously by using other methods.…”

“…Previous studies have adopted analogous approaches by overexpressing ␣-integrins or retinoic receptor-␤2, in either in vitro or dorsal root injury paradigms (25)(26)(27). However, these studies (25)(26)(27) utilized cell systems in which regeneration had been achieved previously by using other methods. Whether conveyance of novel sensitivity to receptor signaling mechanisms can enhance regeneration of refractory adult neurons intrinsic to the CNS has not been explored to date.…”