Ghazi-Nouri, S.M.S.; (2008) Expression of brain derived neurotrophic factor (BDNF), neurotrophin 4 (NT4) and their common receptor, TrkB, by human Muller cells in vitro and vivo. Doctoral thesis , University of London.

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Abstract

Neurotrophins are trophic and mitogenic proteins that play a role in the development, differentiation, connectivity and survival of neurons, acting via their specific receptors in the central and peripheral nervous system, including the retina. The preferred receptor for brain derived neurotrophic factor (BDNF) and neurotrophin 4 (NT4) is TrKB. Muller cells may play an important role in neurotrophin function in the nervous system. It has been suggested that neurotrophins exert their effects on photoreceptors by acting indirectly through activation of Muller cells. The aims of the present work were to characterise the expression of BDNF, NT4 and TrkB by human Muller cells in vitro, and to examine whether changes in the expression of these molecules occur in retina from patients with proliferative vitreoretinopathy (PVR) when compared with normal retina. In addition, changes in the expression of BDNF, NT4 and glial fibrillary acidic protein (GFAP) were also investigated in melanoma affected human retina following laser photocoagulation. A variety of techniques were employed to investigate the expression of the above neurotrophins and TrkB at the RNA and protein levels. These included cell culture and mRNA extraction, RT-PCR, Western blot, and Immunocytochemistery. Confocal laser scanning microscopy and light microscopy were used for imaging. The results showed that cultured human Muller cells express BDNF and NT4 as indicated by both mRNA and protein expression. A truncated isoform of TrkB was also shown to be expressed by a spontaneously immortalized human Muller cell line used in the study (MIO-M1). Staining for NT4 was greatly increased in retinal sections from eyes with PVR, compared with normal retina. NT4 expression by Muller cells in situ was confirmed by confocal imaging observations that cells staining for this neurotrophin co-stained for GFAP. By contrast, there was a decrease in TrkB immunostaining in PVR retinectomy sections compared with controls. NT4 staining was also reduced at the site of laser burns in melanoma affected retina. Possible explanations are discussed in the thesis.

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