Chromaffin cells, the neuroendocrine cells of the adrenal medulla and paraganglia, occupy paradigmatic roles in molecular, cellular and developmental neurobiology. The fact that they are very effective 'minipumps', secreting numerous bioactive substances including amines, neuropeptides and proteins, has made them interesting and useful for the treatment of chronic pain and Parkinsonism. An essential advantage of chromaffin cells is that they can be isolated and purified in extremely high numbers, which can never be achieved for peripheral or central nervous system neurons. Growth factors (cytokines) and peptides with growth factor-like efficacies constitute an important component of bioactive materials released from chromaffin cells. Not only their presence, but also neural and humoral mechanisms regulating their expression and release, are now being revealed. Prominent examples include fibroblast growth factors (FGFs), transforming growth factor-beta s (TGF-beta s) and interleukins. Functions that can be assigned to these factors in the adrenal medulla are gradually emerging. For example, FGFs and TGF-beta s can regulate chromaffin cell proliferation and differentiation and participate in the neurotrophic maintenance of neurons innervating chromaffin cells. In contrast, the functions of the predominant secretory proteins of chromaffin cells, the chromogranins, are still largely unknown, but might include cytokine-like roles. Thus, chromaffin cells continue to teach neurobiologists about the fundamental capacity of neurons to secrete bioactive molecules with a wide range of functions as well as modes of their secretion underscoring the close relationship of endocrine and neuronal systems.

Adrenal Medulla↗

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Neural functions of the transforming growth factors beta.

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Co-activation of TGF-ss and cytokine signaling pathways are required for neurotrophic functions.

This article summarizes and interprets recent data from our laboratories suggesting that transforming growth factor-ss (TGF-ss1, -ss2, -ss3) is essentially required, in vitro and in vivo, for the neurotrophic signaling of glial cell line-derived neurotrophic factor (GDNF). TGF-ss, which is synthesized by and released from neurons, also synergizes with neurotrophins and members of the neurokine and fibroblast growth factor families by increasing their efficacies. However, when applied to purified neuron populations without other factors being added, TGF-ss does not promote survival or differentiation. Together, these data suggest that neither TGF-ss nor GDNF fulfil essential criteria of a typical neurotrophic factor, as e.g. nerve growth factor (NGF). Moreover, the neurotrophic activity of NGF and other classic neurotrophic factors is apparently based, to a significant extent, on their co-operativity with TGF-ss. Mechanisms, by which TGF-ss generates neurotrophic effects and synergizes with other cytokines are beginning to emerge. Recruitment and/or stabilization of receptors and cross-talks at different levels of signal transduction are likely to be implied in generating the neurotrophic potential of the TGF-ss/cytokine synergisms. Together, these data outline a novel role of TGF-ss in a key event of nervous system development, ontogenetic neuron death. Conceptually more important, however, may be the broadening of the neurotrophic factor concept, which now has to imply the possibility that two cytokines, each being ineffective by itself, become neurotrophically active when acting in concert.

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CNTF rescues motoneurons from ontogenetic cell death in-vivo, but not in-vitro.

We studied the effect of CNTF (ciliary neurotrophic factor, human recombinant and chick) on the survival of motoneurons in the embryonic chick lumbar spinal cord during the period of ontogenetic cell death. Daily applications of 5 micrograms CNTF to the chorionic-allantoic membrane from embryonic day 6 (E6) to E9 maintained approximately 15,500 motoneurons as opposed to 13,200 in controls. In contrast, CNTF failed to promote the survival of cells in spinal cord cultures enriched for motoneurons. These results suggest that CNTF may regulate motoneuron survival in-vivo, but its mode of action remains to be elucidated.

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