Deletion of the mouse RegIIIβ (Reg2) gene disrupts ciliary neurotrophic factor signaling and delays myelination of mouse cranial motor neurons

Tebar, Luis; Géranton, Sandrine M; Parsons-Perez, Cristina; Fisher, AJ; Bayne, Rosemary A. L.; Smith, Andrew J.H.; Turmaine, M; Pérez-Luz, Sara; Sheasby, A.; Felipe, Carmen De; Ruff, Crystal A.; Raivich, Gennadij; Hunt, Stephen P.

doi:10.1073/pnas.0711978105

Cited by 26 publications

(21 citation statements)

References 43 publications

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“…Evidence of CNTF autocrine effect on Schwann cells or oligodendrocytes has been reported, although data have been controversial. Disrupted CNTF signaling delays myelination of mouse cranial motor neurons, 23 however, CNTF fails to promote myelination in vivo. 24 Here, we show that CNTF gene transfer to Schwann cells increases expression of myelin proteins and activates their differentiation in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Schwann cell targeting via intrasciatic injection of AAV8 as gene therapy strategy for peripheral nerve regeneration

et al. 2011

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Efficient transduction of the peripheral nervous system (PNS) is required for gene therapy of acquired and inherited neuropathies, neuromuscular diseases and for pain treatment. We have characterized the tropism and transduction efficiency of different adeno-associated vectors (AAV) pseudotypes after sciatic nerve injection in the mouse. Among the pseudotypes tested, AAV2/1 transduced both Schwann cells and neurons, AAV2/2 infected only sensory neurons and AAV2/8 preferentially transduced Schwann cells. AAV2/8 expression in the sciatic nerve was detected up to 10 weeks after administration, the latest time point analyzed. The injected mice developed neutralizing antibodies against all AAVs tested; the titers were higher against AAV2/1 than AAV2/2 and were the lowest for AAV2/8, correlating with a higher transgene expression overtime. AAV2/8 coding for ciliary neurotrophic factor (CNTF) led to an upregulation of P0 and PMP22 myelin proteins, four weeks after transduction of injured sciatic nerves. Importantly, CNTF-transduced mice showed a significant increase in both GAP43 expression in sensory neurons, a marker of axonal regeneration, and the compound muscle action potential. These results prove the utility of AAV8 as a gene therapy vector for Schwann cells to treat myelin disorders or to improve nerve regeneration.

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Section: Discussionmentioning

confidence: 99%

Schwann cell targeting via intrasciatic injection of AAV8 as gene therapy strategy for peripheral nerve regeneration

et al. 2011

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“…Although the expression of Reg-IIIb in motor neurons and the dorsal root ganglion (DRG) during development has been described (Livesey et al, 1997;Nishimune et al, 2000;Tebar et al, 2008), the overall expression profiles of these proteins during development have not. For the Reg-III family members, most information has been collated based on expression of Reg-IIIb and Reg-IIIc; thus in this report we focused on these two molecules and examined their expression profiles by using in situ hybridization and immunohistochemistry during mouse development.…”

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confidence: 99%

Expression analysis of the regenerating gene (Reg) family members Reg‐IIIβ and Reg‐IIIγ in the mouse during development

Matsumoto

Konishi

Maeda

et al. 2011

J of Comparative Neurology

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The regenerating gene/regenerating islet-derived (Reg) family is a group of small secretory proteins. Within this family, Reg type-III (Reg-III) consists of: Reg-IIIα, -β, -γ, and -δ. To elucidate the physiological relevance of Reg-III, we examined the localization and ontogeny of Reg-IIIβ and Reg-IIIγ in mice at different time points spanning from embryonic day 13.5 to 7 weeks old, using in situ hybridization and immunohistochemistry. Our results showed that Reg-IIIβ was expressed in specific subsets of primary sensory neurons and motor neurons, and that expression was transient during the embryonic and perinatal periods. Reg-IIIβ expression was also observed in absorptive epithelial cells of the intestine. In contrast, Reg-IIIγ expression was mainly observed in epithelial cells of the airways and intestine, but not in the nervous system, and expression levels showed a gradually increasing pattern along with development. In the airways Reg-IIIγ was expressed in goblet and Clara-like cells, whereas in the intestine Reg-IIIγ was expressed in the absorptive epithelial cells and Paneth cells, and was found to be expressed in development before these organs had been exposed to the outside world. The present findings imply that Reg-IIIβ and Reg-IIIγ expression is regulated along divergent pathways. Furthermore, we also suggest that expression of Reg-IIIγ in the airway and intestinal epithelia may occur to protect these organs from exposure to antigens or other factors (e.g., microbes) in the outer world, whereas the transient expression of Reg-IIIβ in the nervous system may be associated with the development of the peripheral nervous system including such processes as myelination.

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“…However, the dynamics of Reg-2 expression in rats are different from that of RegIII in mice. Thus, RegIII does not reappear in the adult mouse after transection of the facial or sciatic nerve, and it does not decrease 24 hr after axotomy, as seen following sciatic transection in neonatal rats (Averill et al, 2002;Schweizer et al, 2002;Tebar et al, 2008).…”

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Effects of Reg‐2 on Survival of Spinal Cord Neurons In Vitro

Fang

Huang

Shao

et al. 2010

The Anatomical Record

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Regeneration gene protein 2 (Reg-2) is a small secreted protein expressed in motor and sensory neurons of spinal cord during developmental stages and following injury of peripheral nerves. Reg-2 appears to act as a neurotrophic factor and protects injured neurons from death during regeneration. To illustrate these potential protective effects in vitro, we investigated the blocking effects of Reg-2 antibodies on the survival of primary cultured spinal cord neurons and astrocytes, as well as on neurite outgrowth. In addition, the effects of Reg-2 in neuron injury models induced by peroxide and mitochondrial poisoning were assessed. Our results showed that Reg-2 antibody markedly reduced survival and neurite outgrowth from neurons, whereas astrocyte survival was unaffected. Addition of Reg-2 into the culture medium had no effect on neuron survival or neurite outgrowth. However, the addition of the Reg-2 into culture media after peroxide treatment or cellular hypoxia insult induced by mitochondrial poisoning can reduce lactate dehydrogenase release levels and cell death. Thus, the data suggests that Reg-2 is essential for the survival and neurite outgrowth of developing spinal cord neurons but not the survival of glial cells, and that Reg-2 plays protective effects on spinal cord neurons against injury in vitro. Anat Rec, 293:464-476, 2010. V V C 2010 Wiley-Liss, Inc.

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Deletion of the mouse RegIIIβ (Reg2) gene disrupts ciliary neurotrophic factor signaling and delays myelination of mouse cranial motor neurons

Cited by 26 publications

References 43 publications

Schwann cell targeting via intrasciatic injection of AAV8 as gene therapy strategy for peripheral nerve regeneration

Schwann cell targeting via intrasciatic injection of AAV8 as gene therapy strategy for peripheral nerve regeneration

Expression analysis of the regenerating gene (Reg) family members Reg‐IIIβ and Reg‐IIIγ in the mouse during development

Effects of Reg‐2 on Survival of Spinal Cord Neurons In Vitro

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