Journal of Neuroendocrinology, 1995. Vol. 7, 957-964 zyxwvuts Dexamethasone Regulates the Expression of Neuronal Properties of a Rat lnsulinoma Cell Line Fouad Atouf, Abdelali Tazi, Michel Polak, Paul Czernichow and Raphael Scharfmann INSERM CJF 93-1 3, Hospital R. Debre. 48 Bd Serurier, 7501 9 Paris, France Key words: beta cells, dexamethasone, nerve growth factor receptors, neurofilaments. Abstract Insulin producing cells of the pancreas (beta cells) and neuronal cells share a large number of similarities. For example, different molecules, thought to be specific of neuronal cells, are expressed by beta cells. The factors regulating the expression of these molecules in beta cells are poorly understood. In the present work, we have studied the effect of dexamethasone, a synthetic glucocorticoid, on the expression of three different neuronal traits expressed by INS-1 cells, a highly differentiated beta cell line. We demonstrate that dexamethasone treatment decreases the steady state levels of mRNAs coding for both the low-and the high-affinity NGF receptors and of mRNA coding for NF-H, an intermediate neurofilament specific of neurons. This effect was time-dependent, the decrease being detectable after 4-8 h treatment. The decrease in NGF receptors mRNAs steady state levels was paralleled by a decrease in the number of NGF binding sites as demonstrated after Scatchard analysis. We further focused on the mechanisms by which dexamethasone affects the expression of the low affinity NGF receptor. The effect is countered by the glucocorticoid antagonist RU486, indicating that it is mediated by the glucocorticoid receptor. Finally, the decrease in the low-affinity nerve growth factor receptor mRNA steady state level after dexamethasone treatment is not due to mRNA destabilization but can be rather explained through a change in gene transcription. zyxwvutsrqpon Whereas it is now currently accepted that beta cells (insulin- producing cells of the endocrine pancreas) do not derive from the neural crest (I, 2), beta cells share with neurectoderm-derived cells many common characteristics zyxwvutsrq (3). For example, glutamic acid decarboxylase, involved in the brain in the synthesis of gamma-aminobutyric acid, the main inhibitory neurotransmitter, is also present in beta cells (4). Thyrotropin-releasing hormone (TRH), a hypothalamic releasing factor, is expressed by beta cells during fetal and neonatal life (5, 6). Neurofilament, an intermediate filament specific to neurites, is present in dissociated pancreatic islet cells, which can extend neural-like processes (2). In addition, we have previously demonstrated that beta cells, both in vitro and in vivo, express functional receptors for Nerve Growth Factor (NGF) (7, 8). In beta cells, it has been shown that the expression of neuronal traits is tightly regulated. For example, the pancreatic expression of TRH is developmentally controlled, the TRH concentrations being maximal during neonatal life and decreasing thereafter (5, 6). The expression of NGF receptors is also controlled zyxwvut in vivo, the cell types expressing these receptors being different between fetal and adult life (9). However the factors implicated in this regulation are poorly understood. We have previously shown that in vitro, in beta cell lines, the expression of both the low- and the high-affinity NGF receptors ( ~ 7 5 ~ ~ ~ ~ and Trk-A respectively) is tightly controlled in a positive fashion by somatolactogenic hormones ( 10). These results suggest that these hormones could represent one of the mechanisms by which the sensitivity of beta cells to NGF is increased. In neural crest derived cells, glucocorticoids have been shown to extinguish the neuronal properties of the cells. For example, treatment of bipotential sympathoadrenal cells with dexametha- sone inhibits their neuronal properties and induces their differen- tiation into chromaffin cells (11). To define whether such an inhibitory effect of glucocorticoids would exist in beta cells, we have now studied the effect of dexamethasone, a synthetic gluco- corticoid on three different neuronal traits: p75NGFR and Trk-A, the low and the high affinity N G F receptor respectively (12-15); NF-H, the high molecular mass intermediate neurofilament ( 16). z As an experimental system, we have used the rat beta cell line INS-I, a highly differentiated rat insulin-producing cell line ( 17). We demonstrate that in INS-1 cells, dexamethasone decreases the expression of p75NGFR, Trk-A, and NF-H mRNAs steady state levels. The effect of dexamethasone on p75NGFR gene expression is time and dose-dependent. It is not mediated through destabiliza- tion of p75NGFR mRNA but rather through a change in gene transcription. This work provides a new evidence that in vitro, the neuronal markers expressed by beta cells are tightly regu- lated. Correspondence fo: Dr Raphael Scharfmann, INSERM CJF 93-13 Hospital Robert Debre, 48 Bd SCrurier 75019, Paris, France. zyx 0 1995 Blackwell Science Ltd