Beta cells originate from precursor cells in the pancreatic ducts, although the possibility of an early migration of the neuroectodermal cells to the endoderm has not been completely ruled out [1±3]. These cells share many similarities with neurons such as the expression of neuron-specific molecules, that is tyrosine hydroxylase or dopamine b-hydroxylase. They are electrically excitable like neurons and insulin release is a process resembling neurotransmitter release, involving cell depolarization and vesicle exocytosis [4]. Beta cells and neuronal cells could be sensitive to the same growth and differentiation factors since specific transcriptional activators (Islets1, Pax-6 and Beta2) are expressed in beta cells and neurons, whereas the transcriptional repressor factor NRSF/ Diabetologia (2001) Abstract Aims/hypothesis. Using primary cultures of human pancreatic islets, purified human pancreatic beta cells and the mouse bTC6-F7 cell line, we analysed the expression of nerve growth factor, (NGF/NGF) receptors in beta cells. To investigate whether NGF could sub-serve an autocrine antiapoptotic role in beta cells, we studied the effects of NGF withdrawal using a neutralizing monoclonal anti-NGF antibody.Methods. The expression of NGF and NGF receptors (gp140 Trk-A and p75 NTR ) were analysed by RT-PCR and immunofluorescence. Pulse-chase experiments and beta cell/PC12 co-cultures were used to investigate NGF production and secretion from beta cells. Possible apoptosis induced by NGF withdrawal was monitored by phosphatidylserine translocation, nucleosomal formation, DNA laddering and FACS analysis. Involvement of transcription/translation mechanisms were investigated as well as the gp140Trk-A required. Finally, signal transduction pathways typically involved in apoptotic mechanisms were analysed by western blot analysis.Results. We show that NGF and both NGF receptors, gp140Trk-A and p75 NTR are expressed in beta cells where NGF is produced and secreted in a biologically active form. NGF-withdrawal induces beta-cell transcription/translation independent apoptosis but mediated by gp140Trk-A. Analysis of signal transduction pathways revealed that NGF withdrawal inhibits the PI3-K, protein kinase B (AKT), Bad survival pathway and activates c-Jun kinase (JNK) whereas ERKs and p38 mitogen-activated protein kinase (MAPK) are not affected. Moreover, Bcl-XL, but not Bcl-2 protein expression are reduced. Conclusion/interpretaiton. We suggest that the integrity of the NGF/NGF receptor system and NGF bioavailability participate in controlling beta-cell survival in culture which represents a key issue for improving possibilities for transplantations in the treatment of diabetes. [Diabetologia (2001