Retinoic acid signaling after nerve injury

Experiments with sciatic nerve lesions and spinal cord contusions have demonstrated that retinoic acid is involved in the physiological reactions after PNS and CNS injuries. The aim of this thesis was to identify the cellular targets of injury-related RA signals in the peripheral and central nervous system and to investigate the functional significance of RA in this context.I discovered that crucial components of the RA signal transduction cascade (retinoic acid receptors, retinoid X receptors, RALDH2, Cyp26A1, CRABP-II) were present in Schwann cell primary cultures isolated from newborn rats. After RA treatment the spatial distribution of RXRs and CRABP-II but not from RARs changed from a cytosolic to a nuclear localization, and CRABP-II was downregulated via RA. In the search for possible genetic targets of RA signaling I detected that NGF, BDNF, GDNF, CNTF, TGFb1, TGFb2, TGFb3, IFNb, IFNg and MIF were expressed in Schwann cells. No differential regulation via RA or activation of intracellular signaling cascades of neuropoietic cytokines or neurotrophins was seen.Spinal cord contusion injuries were performed to identify possible cellular targets of RA after damage of the CNS. Cellular distribution and protein levels of all retinoid receptors in the rat spinal cord were investigated 4, 7, 14 and 21 days after injury. I detected immunoreactivity of RARa, RXRa, RXRb and RXRg. In the non-lesioned spinal cord, immunoreactivity of RARa, RXRa, RXRb and RXRg was localized in the cytosol of neurons, of RXRa and RXRb in astrocytes, and of RARa, RXRa and RXRg in some oligodendrocytes. After contusion injury a transient nuclear shift of RARa and of all RXR was visible in reactive microglia/macrophages. This nuclear staining, already seen at 4 days, was most prominent at 7 and 14 days after injury. A similar change in intracellular distribution was also observed for the RARa, RXRa and RXRb staining in neurons situated around the border of the contusion. The injury-induced subcellular translocation was strongest for RARa, while the intracellular distribution of RXRg did not change.While the identification of the cellular targets of RA signaling confirm the hypothesis of an involvement of RA in nerve injury-related processes, the functional significance of RA signaling in Schwann cells remains to be elucidated. In the CNS it seems likely that RA fulfills neuroprotective functions and contributes to the termination of the inflammatory response. A complete understanding of these processes might help to develop strategies to heal neurodegenerative diseases and traumatic injuries.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2005

Author dc:creator

• Schrage, Kirsten

Contributors dc:contributor

• Mey, Jörg

• info:eu-repo/classification/ddc/610
• Medizin
• Regeneration
• Retinoidrezeptoren
• Ratte
• Gliazellen
• subzelluläre Lokalisation
• retinoid receptors
• rat
• subcellular localization
• glia

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-122233%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:60528