Research Report Tissue distribution of Ret, GFRalpha-1, GFRalpha-2 and GFRalpha-3 receptors in the human brainstem at fetal, neonatal and adult age Marina Quartu, Maria Pina Serra, Marianna Boi, Maria Teresa Ferretti, Maria Letizia Lai, Marina Del Fiacco ⁎ Department of Cytomorphology, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, Italy ARTICLE INFO ABSTRACT Article history: Accepted 30 July 2007 Available online 9 August 2007 Occurrence and localization of receptor components of the glial cell line-derived neurotrophic factor (GDNF) family ligands, the Ret receptor tyrosine kinase and the GDNF family receptor (GFR) alpha-1 to -3, were examined by immunohistochemistry in the normal human brainstem at fetal, neonatal, and adult age. Immunoreactive elements were detectable at all examined ages with uneven distribution and consistent pattern for each receptor. As a rule, the GFRalpha-1 and GFRalpha-2 antisera produced the most abundant and diffuse tissue labelling. Immunoreactive perikarya were observed within sensory and motor nuclei of cranial nerves, dorsal column nuclei, olivary nuclear complex, reticular formation, pontine nuclei, locus caeruleus, raphe nuclei, substantia nigra, and quadrigeminal plate. Nerve fibers occurred within gracile and cuneate fasciculi, trigeminal spinal tract and nucleus, facial, trigeminal, vestibular and oculomotor nerves, solitary tract, medial longitudinal fasciculus, medial lemniscus, and inferior and superior cerebellar peduncles. Occasionally, glial cells were stained. Age changes were appreciable in the distribution pattern of each receptor. On the whole, in the grey matter, labelled perikarya were more frequently observed in pre- and perinatal than in adult specimens; on the other hand, in discrete regions, nerve fibers and terminals were abundant and showed a plexiform arrangement only in adult tissue; finally, distinct fiber systems in the white matter were immunolabelled only at pre- and perinatal ages. The results obtained suggest the involvement of Ret and GFRalpha receptors signalling in processes subserving both the organization of discrete brainstem neuronal systems during development and their functional activity and maintenance in adult life. © 2007 Elsevier B.V. All rights reserved. Keywords: GDNF family ligand receptor Man Medulla oblongata Pons Mesencephalon Immunohistochemistry 1. Introduction The receptor complex for the trophins of the glial cell line- derived neurotrophic factor (GDNF) family comprises a com- mon signalling component, the transmembrane receptor tyro- sine kinase Ret (Baloh et al., 2000; Airaksinen and Saarma, 2002), and an extrinsic protein belonging to a family of gly- cosyl phosphatidylinositol (GPI)-linked receptors, called GDNF family receptor alpha (GFRalpha), which behaves as the ligand binding element. Four distinct specific GFRalpha receptors, GFRalpha-1 to GFRalpha-4, have been identified, which me- diate the influence of the GDNF family trophins on the dev- elopment, differentiation, and maintenance of mature phenotype of distinct and partially overlapping central and BRAIN RESEARCH 1173 (2007) 36 – 52 ⁎ Corresponding author. Fax: +39 070 6754003. E-mail address: dfiacco@unica.it (M. Del Fiacco). 0006-8993/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2007.07.064 available at www.sciencedirect.com www.elsevier.com/locate/brainres