The glial cell line-derived neurotrophic factor family in the olfactory system and brain

Glial cell line-derived neurotrophic factor (GDNF) family signaling has been implicated in development, survival and function of many different cell types, including neurons in the central nervous system. The family consists of four ligands [GDNF, neurturin (NTN), artemin and persephin] which bind to four co-receptors (GFRα1-4) and recruit the tyrosine kinase receptor RET into the signaling complex. In vivo, the ligands bind to the co-receptors with preferential affinity, e.g., GDNF to GFRα1 and NTN to GFRα2, whereas in vitro, cross-talk between the ligands and co-receptors has been demonstrated. RET exists as two main alternatively spliced isoforms, RET9 and RET51. These isoforms differ in their carboxyl termini and have been implicated with distinct functions in the enteric and central nervous systems. Clinically, GDNF and NTN have been examined as potential therapeutic agents for treatment of neurodegenerative disorders, particularly Parkinson’s disease (PD), as these proteins were found to provide essential trophic support to dopaminergic (DA) neurons, one of the main neuronal populations affected by this pathology. To progress development of such therapies further, a greater understanding of GDNF family signaling is necessary, which was the aim of the current work. Two regions of the brain were studied -- the olfactory system, a unique region of the nervous system that supports lifelong neurogenesis; and the substantia nigra (SN), the site of DA neuron degeneration in PD. Expression of GDNF, NTN, GFRα1 and GFRα2 was previously characterized in the olfactory system (Maroldt et al., 2005; Kaplinovsky and Cunningham, 2011). The current work specifically focused on expression of the RET isoforms in this system. Double-labeling fluorescent immunohistochemistry in vivo and in an olfactory cell culture model illustrated RET9 to be the predominantly expressed isoform in a pattern similar to the previously reported expression for GDNF and GFRα2. RET51 was generally expressed in a subset of RET9-positive cells and in vivo 2 restricted to the same region as NTN. Treatment of the olfactory cultures with GDNF initiated a strong neurogenerative response, potentially by acting on the GFRα2/RET9 signaling complex. NTN exposure promoted olfactory progenitor proliferation, again potentially via the GFRα2/RET9 signaling complex, as well as differentiation towards a nestin-positive non-neuronal lineage, speculated to be sustentacular or olfactory ensheathing cells. The differentiating affect may have been propagated by GFRα1/RET51 as these proteins were expressed in the same cells in culture. In the adult rat and human SN, RET9 was again found to be the predominantly expressed isoform, localized to all DA neurons, even in PD pathology. RET51 was expressed in a subset of RET9-positive DA neurons in the rat. In human tissue, this isoform was virtually absent from healthy SN whereas in PD, a strong up-regulation was noted in DA neurons as well as s100B-positive glia. The results of this study demonstrate several important features regarding GDNF family signaling mechanisms. First, RET9 was established as the main functional isoform and RET51 as a secondary receptor likely important for a specialized role in a subset of the RET9-positive cells. Second, GDNF may promote neural differentiation by activating the GFRα2/RET9 signaling complex whereas NTN activation of this complex yields proliferative mechanisms. NTN acting on GFRα1/ RET51, however, may cause differentiation towards a supporting cell lineage. Third, RET51 signaling may be involved in the glial response associated with PD pathology. The current study provided evidence for distinct functional roles between the ligands GDNF and NTN, and illustrated the signaling complexes which may be involved in promoting these functions. These findings may facilitate future therapy development for PD as well as other neurodegenerative disorders.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2015

Author dc:creator

• Kaplinovsky, Tamila

• Parkinson's Disease
• GDNF
• RET

Statement dc:rights

• open access
• CC BY-NC-ND 3.0
• free_to_read

Licence

• https://purl.org/coar/access_right/c_abf2
• https://creativecommons.org/licenses/by-nc-nd/3.0/au/

Language dc:language

EN

Identifier

https://doi.org/10.26190/unsworks/18816

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/55676