Localization of GDNF/neurturin receptor (c-ret, GFR alpha-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 ne urotrophic factor, glial cell line-derived neurotrophic factor (GDNF) and i ts homolog, neurturin (NTN), comprising the signaling tyrosine kinase, Ret and multiple GPI-linked binding proteins, GDNF family receptor alpha-1 and alpha-2 (GFR alpha-1 and GFR alpha-2). In the present study the localizatio n of c-ret and GFR alpha-1 and GFR alpha-2 mRNAs was assessed in the develo ping rat brain from postnatal day 4 to 70 by in situ hybridization histoche mistry, using specific [S-35]-labeled oligonucleotides. GFR alpha-1 and GFR alpha-2 mRNAs were differentially distributed throughout the brain at all ages studied, particularly in cerebral cortex, hippocampus, substantia nigr a and regions of the thalamus and hypothalamus - both distributions overlap ping but different to that of c-rer 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 cer ebellum. GFR alpha-1 mRNA was abundant in dorsal endopiriform nucleus, medi al habenula, reticular thalamic nucleus, pyramidal and granule cell layers of the hippocampus, substantia nigra pars compacta and in cranial motor nuc lei. GFR alpha-2 mRNA was highly expressed in many regions including olfact ory bulb, lateral olfactory tract nucleus, neocortical layers IV and VI, se ptum, zona incerta, and arcuate and interpeduncular nuclei. GFRa-2 mRNA was detected in the pyramidal cell layers (CA3) of hippocampus at P4 and P7, b ut was no longer delectable at P14 and beyond, including P70 (adult). GFR a lpha-2 mRNA was also detected in Purkinje cells throughout the cerebellum i n young postnatal rats, but was enriched in the posterior lobes at P28 and P70. These localization studies support evidence of GDNF/NTN as target-deri ved and autocrine/paracrine trophic factors in developing brain pathways an d earlier suggestions of unique and complex signaling mechanisms for these factors via a family of receptors. Strong expression of GFR alpha-1 and GFR alpha-2 mRNAs in adult brain suggests possible non-trophic functions of GD NF/NTN, as described for other neurotrophins, such as brain-derived neurotr ophic factor. (C) 1999 Elsevier Science B.V. All rights reserved.