Differential expression of RET receptor isoforms in the olfactory system

The glial cell line-derived neurotrophic factor (GDNF) family supports neurons by activating the tyrosine kinase receptor RET. The two main isoforms of RET, RET9 and RET51, differ in their carboxyl termini and have been implicated with distinct functions in the enteric and central nervous systems. Previously we reported the cellular localization of GDNF, neurturin and RET9 in the olfactory system [Maroldt H, Kaplinovsky T, Cunningham AM (2005) J Neurocytol 34:241-255]. In the current study, we examined immunohistochemical expression of RET9 and RET51 in neonatal and adult rat olfactory neuroepithelium (ON) and bulb to explore their potential functional roles. In the ON, RET9 was expressed by olfactory receptor neurons (ORNs) throughout the olfactory neuroepithelial sheet, whereas RET51 was restricted to ORNs situated in ventromedial and ventrolateral regions. Within these regions, RET51 was expressed by a subset of RET9-expressing ORNs. In olfactory bulb, RET9 expression was primarily on cell bodies, including olfactory ensheathing and periglomerular cells, and again, RET51 was expressed by a subset of RET9-expressing cells. RET51 was identified on axons in the olfactory nerve layer and glomerular neuropil, but only in the ventromedial and ventrolateral regions of the bulb. This regionalization correlated with the predicted axonal projection from expressing regions of the ON. RET51 was also expressed on dendrites in the external plexiform layer and glomerular neuropil. These results suggest RET9 may be the predominant functional isoform in the ON while RET51 plays a more selective role in a restricted region of the olfactory neuroepithelial sheet. In the bulb, RET9 is likely the main functional isoform while RET51 may be important in axonal and dendritic function/targeting.