The Neuroendocrine Concept Today

In 1938, Friedrich Feyrter, using classical histological staining methods, reported the presence of a variety of rather pale cells (Helle Zellen) distributed widely throughout the body, particularly in the intestinal tract. ’ He grouped these together, suggesting that they constituted a single “diffuse endocrine system,” and was thus the first to crystallize ideas on how isolated single cells or small groups of cells widely dispersed in tissues outside the brain could secrete “blood borne chemical messengers,” which exert an influence either on their neighbors in a paracrine fashion or at more distant sites in an endocrine fashion, notions that had been propagated much earlier by Bayliss and Starling.z Little more was written on the subject until major developments in the field of histochemistry and the increasing application of the electron microscope to biological specimens in the late 1950s and 1960s led Everson Pearse to conclude that a number of cells, with the common function of producing polypeptide hormones, shared a variety of cytochemical and ultrastructural characteristics. He formulated the first version of his neuroendocrine concept by grouping these cells together under the acronym APUD, amine-precursor uptake decarboxyl a ~ e . ~ . ~ This classification unifying widely separated cells, present either in classical endocrine organs or isolated in sites dispersed throughout the body, forms the basis of what we understand today as the diffuse neuroendocrine system. As had been postulated by Bayliss and Starling,* he too considered these cells to function by secreting peptides that influenced target cells in their immediate neighborhood or in distant tissues. He went further, however, and this was one of the revolutionary and visionary aspects of his concept; he considered that these cells constituted a novel third branch of the nervous system, designed to complement the autonomic and somatic nervous systems. These cells could act together with the autonomic system in the control of the function of all internal organ^. ^ Peptidergic nerves were subsequently included in this novel concept of the diffuse neuroendocrine system6 Pearse extrapolated this idea by suggesting that all cells constituting this system shared a common embryonic origin, namely the neural crest. Since its initial conception, many data have thrown considerable doubt on the validity of certain of the original criteria that were considered at the outset to be essential, in particular that concerning the embryonic origin of neuroendocrine cells. In spite of this, the 1970s and 1980s saw an explosion in the number of cells included in the list of neuroendocrine cells,’ most of which are not currently considered to arise from the neural crest. In addition, the list of common properties was greatly extended. This was largely due to the development of immunocytochemistry and the production of specific antibodies against the increasing numbers of “neuropeptides” that were discovered: but also to the characterization of “cell-type” markers, in particular those for neural cells.9 The search for proteins commonly expressed by different neuroendocrine cells and by neurons has actively continued over the last ten years. The importance we