Differential recruitment of p160 coactivators by glucocorticoid receptor between Schwann cells and astrocytes.

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Grenier, Julien | Trousson, Amalia | Chauchereau, Anne | Cartaud, Jean | Schumacher, Michael | Massaad, Charbel

Edité par CCSD ; Endocrine Society -

In the nervous system, glucocorticoids (GC) can exert beneficial or noxious effects, depending on their concentration and the duration of hormonal stimulation. They exert their effects on neuronal and glial cells by means of their cognate receptor, the glucocorticoid receptor (GR), which recruits the p160 coactivator family members SRC-1, SRC-2 and SRC-3 after hormone binding. In this study, we investigated the molecular pathways used by the GR in cultured glial cells of the central and the peripheral nervous systems, respectively astrocytes and Schwann cells (MSC80 cells). We performed functional studies based on transient transfection of a minimal GC-sensitive reporter gene into the glial cells to test the influence of overexpression or selective inhibition by siRNA of the three p160 coactivator family members on GR transactivation. We demonstrate that, depending on the glial cell type, GR differentially recruits p160 family members : in Schwann cells, GR recruited SRC-1a, SRC-1e or SRC-3, whereas in astrocytes, SRC-1e and SRC-2, and to a lesser extent SRC-3, were active toward GR signaling. The C-terminal nuclear receptor interacting domain (NR2) of SRC-1a participates in its exclusion from the GR transcriptional complex in astrocytes. Immunolocalization experiments revealed a cell-specific intracellular distribution of the p160s, which was dependent on the duration of the hormonal induction. For example, within astrocytes, SRC-1 and SRC-2 were mainly nuclear, while SRC-3 unexpectedly localized to the lumen of the Golgi apparatus. In contrast, in Schwann cells, SRC-1 showed a nucleo-cytoplasmic shuttling depending on hormonal stimulation, while SRC-2 remained strictly nuclear and SRC-3 predominantly cytoplasmic. Altogether, these results highlight the cell-specificity and the time-dependence of p160s recruitment by the activated GR in glial cells, revealing the complexity of GR-p160 assembly in the nervous system.

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