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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 beta-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.
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The expression of functional receptors for nerve growth factor in insulin-producing cell lines grown in vitro has recently been demonstrated. The possible importance of signals transduced via these receptors in the control of islet maturation has been proposed based on data obtained using an in vitro culture system. To further support this hypothesis, we have studied the expression of Trk-A, the high-affinity receptor for NGF, in vivo during the embryonic and fetal development of the rat pancreas. We have also examined the expression of NGF during the same period. Immunohistological analysis shows that at embryonic day 11 (E11), Trk-A is expressed by the epithelial cells of the presumptive pancreas. The few pancreatic endocrine cells present at that stage express Trk-A. At E12 and E16, Trk-A expression was detected in the developing ductal network. The endocrine cells located in the ducts express Trk-A while those that have migrated into the surrounding mesenchyme now stain negative for Trk-A. By E20, Trk-A expression by ductal cells has considerably decreased and can be detected only in small ducts closely associated with islet-like structures. These islet-like structures stain negative for Trk-A. After birth, insulin-positive cells arranged into islets re-express Trk-A. During the same period, NGF mRNA is found to be expressed in the developing pancreas. The expression of Trk-A and its ligand NGF in the pancreas during embryonic and fetal life suggests that NGF and its receptor could play an important role in the development of the pancreas.
