Publikationsserver der RWTH Aachen University
Retinoic acid signalling after peripheral nerve injury
Abstract
dc:descriptionAlthough the problem of nerve regeneration has been studied since the beginning of the 20th century, the molecular mechanisms of this process are still largely unknown. Recently, the involvement of retinoic acid (RA) signalling was also proposed to regulate PNS regeneration based on its regulation of a variety of intercellular signals, which take part in the physiology of nerve regeneration. However, no experiments have so far been conducted to prove that functional retinoid signalling forms part of the traumatic reactions in PNS. The results of my thesis allow to confirm this hypothesis: With RT-PCR and immunoblotting all necessary components of the RA signalling pathway were detected in the sciatic nerve of adult rats. These are retinoic acid receptors, retinoid X receptors, the retinoic acid synthesising enzymes RALDH-1, RALDH-2 and RALDH-3, and the cellular retinoid binding proteins CRBP-I, CRABP-I and CRABP-II. Although the transcript levels of RALDHs were not significantly altered by a sciatic nerve injury, sciatic nerve crush and transection resulted in a more than 10-fold up-regulation of CRBP-I mRNA, a protein which is thought to facilitate the synthesis of RA. Transcript and protein levels of CRABP-II were elevated 15-fold. This is a possible mediator of RA transfer to its nuclear receptors. The expression of retinoid binding proteins remained elevated during and two weeks after nerve transection, thus the involvement of these proteins in the first phase of axonal regeneration - Wallerian degeneration - may be assumed. Other key molecules of RA regulation are its nuclear receptors, the expression and immunoreactivity of which was measured in the next part of my work. Seven days after crush, the protein levels of RARalpha, RXRalpha and RXRbeta were significantly up-regulated (4-, 2- and 1.5-fold respectively). On the mRNA level, all three RARs and RXRalpha were elevated as well. In order to investigate putative biological effects of RA, Schwann cell were investigated. These cells were found to express all components of the retinoic acid signalling cascade and thus can be the source of RA and the target of its functions. I discovered that retinoic acid autoregulates the gene expression of RARbeta and RARgamma in Schwann cells, as well as the expression of erbB3, an important signalling intermediate during Wallerian degeneration. These findings confirm our hypothesis of an involvement of RA in Wallerian degeneration. However, they rise a number of open questions about the cellular source of RA signalling, the trigger of its activation and the downstream mechanisms of RA action. The answers to these questions in the future will enable the better understanding of the molecular processes of PNS regeneration.
Degree
thesis:*- Grantor dc:publisher
- Publikationsserver der RWTH Aachen University
- Year dc:date
- 2003
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Zhelyaznik, Nina
- Contributors dc:contributor
-
- Mey, Jörg
Subjects
dc:subject × 4Rights
dc:rights- Statement dc:rights
-
- info:eu-repo/semantics/openAccess
- Language dc:language
- eng