Research Article New Insights into c-Ret Signalling Pathway in the Enteric Nervous System and Its Relationship with ALS M. J. Luesma, 1,2 I. Cantarero, 3,4 J. M. Álvarez-Dotu, 5 S. Santander, 6 and C. Junquera 1,2 1 Department of Human Anatomy and Histology, Faculty of Medicine, University of Zaragoza, Domingo Miral, s/n, 50009 Zaragoza, Spain 2 Aragon Health Sciences Institute (I+CS), Zaragoza, Spain 3 Department of Cellular Biology, Physiology and Immunology, Faculty of Medicine, University of C´ ordoba, Spain 4 Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Spain 5 Department of Obstetrics, Gynaecology and Surgery, University of Zaragoza, Spain 6 Department Pharmacology and Physiology, Faculty of Medicine, University of Zaragoza, Spain Correspondence should be addressed to M. J. Luesma; mjluesma@unizar.es Received 23 January 2014; Accepted 7 April 2014; Published 28 April 2014 Academic Editor: Ana Cristina Calvo Copyright © 2014 M. J. Luesma et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Te receptor tyrosine kinase Ret (c-Ret) transduces the glial cell line-derived neurotrophic factor (GDNF) signal, one of the neurotrophic factors related to the degeneration process or the regeneration activity of motor neurons in amyotrophic lateral sclerosis (ALS). Te phosphorylation of several tyrosine residues of c-Ret seems to be altered in ALS. c-Ret is expressed in motor neurons and in the enteric nervous system (ENS) during the embryonic period. Te characteristics of the ENS allow using it as model for central nervous system (CNS) study and being potentially useful for the research of human neurological diseases such as ALS. Te aim of the present study was to investigate the cellular localization and quantitative evaluation of marker c-Ret in the adult human gut. To assess the nature of c-Ret positive cells, we performed colocalization with specifc markers of cells that typically are located in the enteric ganglia. Te colocalization of PGP9.5 and c-Ret was preferentially intense in enteric neurons with oval morphology and mostly peripherally localized in the ganglion, so we concluded that the c-Ret receptor is expressed by a specifc subtype of enteric neurons in the mature human ENS of the gut. Te functional signifcance of these c-Ret positive neurons is discussed. 1. Introduction Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenera- tive disease characterized by selective degeneration of motor neurons located in the spinal cord, brain stem, and motor cortex, resulting in progressive atrophy and paralysis of limb, bulbar, and respiratory muscles [1–5]. Glial cell line-derived neurotrophic factor (GDNF) has been thought to be one of the potent neurotrophic factors related to the degeneration process or the regeneration activity of motor neurons in ALS. In particular GDNF is a member of the transforming growth factor- superfamily which promotes the survival of motor neurons and mesencephalic dopaminergic neurons [6, 7]. Te GDNF signal is transduced by a specifc receptor, the proto-oncogene product RET (a tyrosine kinase recep- tor c-Ret), in association with another receptor GDNFR- (GFR-1) [6, 8–12]. Te phosphorylation of several tyrosine residues of RET is a crucial step in the intracellular signaling pathway [6, 13] and it seems to be altered in ALS [5]. c-Ret is expressed in the restricted tissues including motor neurons determining the specifc distribution of GDNF-responsive neurons, [12]; one of these tissues is the enteric nervous system (ENS) where Ret is highly expressed during the embryonic period. It is a crucial signal for the development of enteric neurons [14–19]. On the other hand, the enteric nervous system (ENS) is a collection of neurons in the gastrointestinal tract that constitutes the “brain of the gut.” Tis system provides neural control for all functions of the gastrointestinal tract. Subsequent examination of the functional and chemical diversity of enteric neurons revealed that the enteric nervous Hindawi Publishing Corporation BioMed Research International Volume 2014, Article ID 328348, 7 pages http://dx.doi.org/10.1155/2014/328348