GFRα 1-2-3-4 co-receptors for RET Are co-expressed in Pituitary Stem Cells but Individually Retained in Some Adenopituitary Cells

Abstract

The RET tyrosine kinase receptor is expressed by the endocrine somatotroph cells of the pituitary where it has important functions regulating survival/apoptosis. However, RET is also expressed by the GPS pituitary stem cells localized in a niche between the adenopituitary and the intermediate lobe. To bind any of its four ligands, RET needs one of four co-receptors called GFRalpha1-4. It has been previously shown that GFRalpha1 is expressed by somatotroph cells and acromegaly tumors. GFRalpha2 was shown to be expressed by pituitary stem cells. GFRalpha4 was proposed as not expressed in the pituitary. Here we study the RNA and protein expression of the four GFRalpha co-receptors for RET in rat and human pituitary. The four co-receptors were abundantly expressed at the RNA level both in rat and human pituitary, although GFRalpha4 was the less abundant. Multiple immunofluorescence for each co-receptor and beta-catenin, a marker of stem cell niche was performed. The four GFRalpha co-receptors were co-expressed by the GPS cells at the niche colocalizing with beta-catenin. Isolated individual scattered cells positive for one or other receptor could be found through the adenopituitary with low beta-catenin expression. Some of them co-express GFRalpha1 and PIT1. Immunohistochemistry in normal human pituitary confirmed the data. Our data suggest that the redundancy of GFRalpha co-expression is a self-supportive mechanism which ensures niche maintenance and proper differentiation.