Localization of GDNF/neurturin receptor (c-ret, GFRalpha-1 and alpha-2) mRNAs in postnatal rat brain: differential regional and temporal expression in hippocampus, cortex and cerebellum.

Recent studies have identified a multi-component receptor system for the neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF) and its homolog, neurturin (NTN), comprising the signaling tyrosine kinase, Ret and multiple GPI-linked binding proteins, GDNF family receptor alpha-1 and alpha-2 (GFRalpha-1 and GFRalpha-2). In the present study the localization of c-ret and GFRalpha-1 and GFRalpha-2 mRNAs was assessed in the developing rat brain from postnatal day 4 to 70 by in situ hybridization histochemistry, using specific [35S]-labeled oligonucleotides. GFRalpha-1 and GFRalpha-2 mRNAs were differentially distributed throughout the brain at all ages studied, particularly in cerebral cortex, hippocampus, substantia nigra and regions of the thalamus and hypothalamus - both distributions overlapping but different to that of c-ret mRNA. C-ret mRNA was abundant in areas such as the lateral habenula, reticular thalamic nucleus, substantia nigra pars compacta, cranial motor nuclei, and the Purkinje cell layer of the cerebellum. GFRalpha-1 mRNA was abundant in dorsal endopiriform nucleus, medial habenula, reticular thalamic nucleus, pyramidal and granule cell layers of the hippocampus, substantia nigra pars compacta and in cranial motor nuclei. GFRalpha-2 mRNA was highly expressed in many regions including olfactory bulb, lateral olfactory tract nucleus, neocortical layers IV and VI, septum, zona incerta, and arcuate and interpeduncular nuclei. GFRalpha-2 mRNA was detected in the pyramidal cell layers (CA3) of hippocampus at P4 and P7, but was no longer detectable at P14 and beyond, including P70 (adult). GFRalpha-2 mRNA was also detected in Purkinje cells throughout the cerebellum in young postnatal rats, but was enriched in the posterior lobes at P28 and P70. These localization studies support evidence of GDNF/NTN as target-derived and autocrine/paracrine trophic factors in developing brain pathways and earlier suggestions of unique and complex signaling mechanisms for these factors via a family of receptors. Strong expression of GFRalpha-1 and GFRalpha-2 mRNAs in adult brain suggests possible non-trophic functions of GDNF/NTN, as described for other neurotrophins, such as brain-derived neurotrophic factor.