Pancreatic acinar AR42J cells express functional nerve growth factor receptors F Miralles, P Czernichow and R Scharfmann INSERM U457, Hospital Robert Debre´, 48, Boulevard Se´rurier, 75019 Paris, France (Requests for offprints should be addressed to F Miralles) Abstract The factors regulating the differentiation of the endocrine cells of the pancreas are still unknown. In previous studies, we have demonstrated that, like neurones, various -cell lines express functional neurotrophin receptors. Moreover, Trk-A, the nerve growth factor (NGF) high-affinity receptor, is expressed in vivo in mature rat islets and early during development in the pancreatic ductal network that represents the source of putative stem cells. Rat pancreatic AR42J cells possess both exocrine and neuroendocrine properties. Recent studies have shown that these cells can differentiate either into acinar cells or into insulin- expressing cells. In this study, we demonstrate that AR42J cells, in common with the embryonic ductal cells, do express Trk-A. Moreover, on treatment with NGF, Trk-A is phosphorylated and early responsive genes such as NGFI-A, c-fos and c-jun are induced. These results clearly show that the Trk-A receptor expressed in AR42J is functional. AR42J cells provide a model system with which to study the role of NGF in the development of the pancreatic cells. Journal of Endocrinology (1999) 160, 433–442 Introduction The endocrine cells of the pancreas exhibit many features in common with those of neurones (Scharfmann 1997). For example, one of the major targets in the immune reaction leading to type I diabetes is the enzyme, glutamic acid decarboxylase, which is present in  cells and neurones and is involved in the synthesis of ª-aminobutyric acid, the main inhibitory neurotransmitter in the brain (Baekkeskov et al. 1990). Given the simi- larities between  cells and neurones, we postulated that these cells and their precursors could be sensitive to the same growth and differentiation factors. Among the factors implicated in neurone differentiation and survival, the best known are the members of the neurotrophin family, which comprises: nerve growth factor (NGF) (Levi-Montalcini 1987), brain-derived neurotrophic factor (BDNF) (Leibrock et al. 1989), neurotrophin-3 (NT-3) (Hohn et al. 1990) and neurotrophin-4/5 (NT-4/5) (Halbook et al. 1991). Two kinds of transmembrane glycoproteins have been identified as receptors for neuro- trophins: p75 NGFR (Chao et al. 1986) and members of the Trk family of tyrosine kinases (Barbacid 1994). p75 NGFR has been described as a low-affinity receptor for all neurotrophins, whereas Trk tyrosine kinases are high- affinity receptors that display neurotrophin specificity: Trk-A acts as a receptor for NGF and NT-3, Trk-B is a receptor for BDNF, and Trk-C binds exclusively NT-3. Recently, our laboratory has demonstrated that both the low- and high-affinity NGF receptors (p75 NGFR and Trk-A respectively) are expressed in different insulinoma- derived cell lines (Scharfmann et al. 1993). Furthermore, we have shown that the NGF receptors expressed by these insulin-secreting cells are functional (Tazi et al. 1995). We have also shown that Trk-A is present in rat pancreas during development and adult life (Kanaka-Gantenbein et al. 1995). During fetal life, a low level of Trk-A expression can be detected in insulin- or glucagon- positive cells by immunohistochemistry, whereas high levels are detected in the ductal cells. In the pancreatic ducts, Trk-A expression progressively decreases as pancreas maturation progresses; in the adult pancreas, Trk-A expression is restricted to the islet cells. Thus the expression and localization of Trk-A in the rat pancreas is developmentally regulated. Pancreatic AR42J cells are derived from a chemically induced rat pancreatic acinar carcinoma. These cells secrete amylase and other digestive enzymes, but they also possess some of the characteristics of neuroendocrine cells (Christophe 1994). For example, AR42J cells have electrically excitable membranes, and express neuro- endocrine markers such as synaptophysin, the protein, SV2, and glutamic acid decarboxylase (Christophe 1994). Logsdon et al. (1985) reported that, after exposure to dexamethasone, these cells lost their neuroendocrine properties, whereas the amylase contents and the number 433 Journal of Endocrinology (1999) 160, 433–442 ? 1999 Society for Endocrinology Printed in Great Britain 0022–0795/99/0160–433 Online version via http://www.endocrinology.org Downloaded from Bioscientifica.com at 04/24/2020 11:07:51AM via free access