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Proopiomelanocortin and melanocortin receptors in the adult rat retino-tectal system and their regulation after optic nerve transection
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
2003 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 482, no 1-3, 85-94 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to characterise the expression of the melanocortin system in the normal and injured rat visual system. Using real-time polymerase chain reaction and immunohistochemistry, we detected melanocortin MC3, MC4 and MC5 receptors and proopiomelanocortin in adult retina and superior colliculus. Melanocortin MC4 receptor mRNA was the most abundant receptor. Melanocortin MC3, MC4 and MC5 receptors were localised to the ganglion cell and inner nuclear layers and the melanocortin MC3 and MC4 receptors were localised to retinal ganglion cells. Transection of the optic nerve leads to ganglion cell death and both melanocortin receptor and proopiomelanocortin expression decreased in superior colliculus after transection whereas the expression was unchanged or even increased in the retina. α-Melanocyte-stimulating hormone elicited neurite outgrowth from embryonic retinal explants. Together, these data implicate a role for the melanocortin system in the adult rat retina and that melanocortins can stimulate neurite growth from retinal neurons.

Place, publisher, year, edition, pages
2003. Vol. 482, no 1-3, 85-94 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-90353DOI: 10.1016/j.ejphar.2003.10.011OAI: oai:DiVA.org:uu-90353DiVA: diva2:162676
Available from: 2003-04-29 Created: 2003-04-29 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Neurotrophic Factor Receptors in the Normal and Injured Visual System: Focus on Retinal Ganglion Cells
Open this publication in new window or tab >>Neurotrophic Factor Receptors in the Normal and Injured Visual System: Focus on Retinal Ganglion Cells
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The focus of this thesis is the life and death of adult retinal ganglion cells (RGCs). RGCs are neurons that convey visual information from the retina to higher centers in the brain. If the optic nerve is transected (ONT), adult RGCs die by a form of cell death called apoptosis, and a general hypothesis is that neurotrophic factors can support the survival of injured neurons.

With the intention to gain knowledge about systems that can be used to decrease RGC death after ONT, we have studied growth factor receptors belonging to the tyrosine kinase family of receptors (RTK), known to mediate important cell survival signals. We found that the RTK Ret and its coreceptor GFRα1 were expressed by RGCs, and to test the above-mentioned hypothesis, we intraocularly administered glial cell-line derived factor, which activates a Ret-GFRα1 complex, and found transiently mediated RGC survival after ONT.

To identify new, potential neurotrophic factor receptors expressed by RGCs, with the aim to improve RGC survival after ONT, we developed a method for the molecular analysis of acutely isolated RGCs. The method involves retrograde neuronal tracing, mechanical retinal layer-separation, and isolation of individual RGCs under UV-light for RT-PCR analysis. Using this method, in combination with degenerate PCR directed towards the tyrosine kinase domain, several RTKs were identified. Axl, Sky, VEGFR-2, VEGFR-3, CSF-1R, and PDGF-βR are expressed by adult RGCs, and considered to be receptors with potential neurotrophic activity. Other results have shown that RGCs may require depolarization or increase in intracellular cAMP levels in order to fully respond to exogenously added trophic factors. We found that melanocortin receptors (MCRs) were expressed by RGCs, and MCRs can mediate elevation of intracellular AMP. We observed that α-MSH induced neurite outgrowth from embryonic retinal cells, indicating that MCR ligands have direct effects on retinal cells. RTKs and their ligands may be involved in endogenous systems for neuronal repair within the visual system. BDNF, NT-3, FGF2, and HGFR all increased in the retina after ONT and may be a part of an activated system for neuronal repair locally within the retina.

Adult axotomized RGCs die by apoptosis, therefore we examined the regulation of apoptotic genes after ONT. Bim and Bax increased in the retina after ONT, and may promote death of axotomized RGCs, whereas the increase in Bcl-2 may contribute to limit RGC apoptosis after ONT.

All in all, this thesis provides insights into the expression and regulation of molecules involved in the death and survival of RGCs. The results have revealed a number of potential neurotrophic receptors expressed by RGCs, and both identified RTKs and MCRs will serve as new targets in therapeutic approaches aiming at counteraction of RGC death after injury.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 71 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1261
Keyword
Neurosciences, cell survival, gene expression, neurotrophic factor, receptor, retina, visual system, Neurovetenskap
National Category
Neurology
Research subject
Developmental Neurosciences
Identifiers
urn:nbn:se:uu:diva-3402 (URN)91-554-5629-4 (ISBN)
Public defence
2003-05-23, B21, BMC, Uppsala, 09:15
Opponent
Supervisors
Available from: 2003-04-29 Created: 2003-04-29 Last updated: 2013-09-19Bibliographically approved

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Lindblom, JonasHallböök, Finn

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