New insights into c-Ret signalling pathway in the enteric nervous system and its relationship with ALS.

M J Luesma,S Santander,J M Álvarez-Dotu,I Cantarero,C Junquera

doi:10.1155/2014/328348

Abstract

The 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). The 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. The 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. The 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 specific markers of cells that typically are located in the enteric ganglia. The 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 specific subtype of enteric neurons in the mature human ENS of the gut. The functional significance of these c-Ret positive neurons is discussed.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative 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 [1,2,3,4,5]
The 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 specific distribution of Glial cell line-derived neurotrophic factor (GDNF)-responsive neurons, [12]; one of these tissues is the enteric nervous system (ENS) where Ret is highly expressed during the embryonic period
The tyrosine kinase receptor c-Ret in association with another receptor GDNFR-α (GDNFRα-1) transduces GDNF mediated signal, which seems to be one of the neurotrophic factors related to ALS [6,7,8,9,10,11,12]

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative 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 [1,2,3,4,5]. 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. C-Ret is expressed in the restricted tissues including motor neurons determining the specific 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 [14,15,16,17,18,19]

Objectives

Methods

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Conclusion