Multidirectional differentiation in neuroendocrine neoplasms

Histopathological and experimental observations indicate that tumors composed wholly or in part of neuroendocrine elements may arise in tissues derived from ectoderm (including neuroectoderm), mesoderm, and endoderm. These tumors frequently exhibit multidirectional differentiation as manifested by multihormonality and by the presence of morphological features indicative of divergent differentiation both in vivo and in vitro. The existence of stem cells, plasticity of differentiated cells, microenvironmental influences, and random events are factors which might all interact to determine the characteristics of any particular tumor. The production of characteristic regulatory peptide products in association with tumors of specific histological subtypes and with other neuroendocrine markers suggests mechanisms for nonrandom activation of multiple genes common to neuroendocrine-programmed cells. Future studies applying new molecular biological techniques to intact tissues and to in vitro models may help to clarify the mechanisms that regulate the expression of the neuroendocrine phenotype in normal and neoplastic states.     

Understanding eating disorders

The outcome in eating disorders remains poor and commonly used methods of treatment have little, if any effect. It is suggested that this situation has emerged because of the failure to realize that the symptoms of eating disorder patients are epiphenomena to starvation and the associated disordered eating. Humans have evolved to cope with the challenge of starvation and the neuroendocrine mechanisms that have been under this evolutionary pressure are anatomically versatile and show synaptic plasticity to allow for flexibility. Many of the neuroendocrine changes in starvation are responses to the externally imposed shortage of food and the associated neuroendocrine secretions facilitate behavioral adaptation as needed rather than make an individual merely eat more or less food. A parsimonious, neurobiologically realistic explanation why eating disorders develop and why they are maintained is offered. It is suggested that the brain mechanisms of reward are activated when food intake is reduced and that disordered eating behavior is subsequently maintained by conditioning to the situations in which the disordered eating behavior developed via the neural system for attention. In a method based on this framework, patients are taught how to eat normally, their physical activity is controlled and they are provided with external heat. The method has been proven effective in a randomized controlled trial.     

Signal transduction mechanisms mediating secretion in goldfish gonadotropes and somatotropes.

The intracellular signal transduction mechanisms mediating maturational gonadotropin and somatotropin secretion in goldfish are reviewed. Several major signaling mechanisms, including changes in intracellular [Ca2+], arachidonic acid cascades, protein kinase C, cyclic AMP/protein kinase A, calmodulin, nitric oxide, and Na+/H+ antiport, are functional in both cell types. However, their relative importance in mediating basal secretion and neuroendocrine-factor-regulated hormone release differs according to cell type. Similarly, agonist- and cell-type-specificity are also present in the transduction pathways leading to neuroendocrine factor-modulated maturational gonadotropin and somatotropin release. Specificity is present not only in the actions of different regulators within the same cell type and with the same ligand in the two cell types, but this also exists between isoforms of the same neuroendocrine factor within a single cell type. Other evidence suggests that function-selectivity of signaling may also result from differential modulation of Ca2+ fluxes from different sources. The interaction of different second messenger systems provide the basis by which regulation of maturational gonadotropin and somatotropin release by multiple neuroendocrine factors can be integrated at the target cell level.     

Formation of the transverse nerve in moth embryos. II. Stereotyped growth by the axons of identified neuroendocrine neurons

We are interested in the cellular mechanisms that guide neuroendocrine axons to their neurohaemal target regions and that regulate the extent and positioning of their terminal arbor. The neurohaemal organ we have studied is the segmentally repeated transverse nerve of the moth Manduca. In the mature animal, two motor neurons and a heterogeneous set of identified neuroendocrine neurons project to this nerve; the latter release hormonal peptides from along its length. In the preceding report, we demonstrated that during embryogenesis, the position, trajectory and extent of the transverse nerve are anticipated by two sets of nonneuronal cells, the strap and the bridge. In this paper we show that four identified neuroendocrine neurons (L1 and B1-3), like the identified motor neurons before them, elaborate growth cones that use this preexisting scaffolding as a substrate for axonal elongation. Moreover, growth cone navigation by these neuroendocrine neurons is as precise and invariant as that displayed by the motor neurons. One feature that differentiates the behavior of the developing neuroendocrine cells from that of the motor neurons is a stereotyped interaction that the L1 and B1-3 axons undergo with an identified syncytial cell that lies in close proximity to the strap. Each neuroendocrine neuron specifically adheres to the syncytium by extending numerous filopodia, and an occasional large lamellopodium, over its surface. These contacts are maintained by the neuroendocrine axons after their growth cones have left the vicinity of the syncytium and proceeded into the strap/bridge complex. Adhesion to the syncytium is transient and specific to the neuroendocrine neurons: although motor neuron axons are present at this same time and place, they display no affinity for the syncytium. This distinction correlates with the fact that the neuroendocrine neurons go on to elaborate arbor within the confines of the transverse nerve, while the motor neurons do not. We suggest that the syncytium may act as a "fictive target" for these neurons to aid in the differentiation of features that are specific to their cellular phenotype.     

Nitric oxide and homeostatic control: an intercellular signalling molecule contributing to autonomic and neuroendocrine integration?

Accumulated evidence indicates that nitric oxide (NO) plays a pivotal role in the central control of bodily homeostasis, including cardiovascular and fluid balance regulation. Two major neuronal substrates mediating NO actions in the control of homeostasis are the paraventricular nucleus (PVN) of the hypothalamus, considered a key center for the integration of neuroendocrine and autonomic functions, and the supraoptic nucleus (SON). In this work, a comprehensive review of NO modulatory actions within the SON/PVN, including NO actions on neuroendocrine and autonomic outputs, as well as the cellular mechanisms underlying these effects is provided. Furthermore, this review comprises recent progress from our laboratory that adds to our current understanding of the cellular sources, targets and mechanisms underlying NO actions within neuroendocrine and autonomic hypothalamic neuronal circuits. By combining in vitro patch clamp recordings, tract-tracing neuroanatomy, immunohistochemistry and live imaging techniques, we started to shed light into the cellular sources and signals driving NO production within the SON and PVN, as well as NO actions and mechanisms targeting discrete neuronal populations within these circuits. Based on this new information, we have expanded one of the current working models in the field, highlighting a key role for NO as a signaling molecule that facilitates crosstalk among various cell types and systems. We propose that this dynamic NO signaling mechanisms may constitute a neuroanatomical and functional substrate underlying the ability of the SON and PVN to coordinate complex neuroendocrine and autonomic output patterns.     

Expression of CFTR and Cl(-) conductances in cells of pulmonary neuroepithelial bodies

The pulmonary neuroendocrine cell system comprises solitary neuroendocrine cells and clusters of innervated cells or neuroepithelial bodies (NEBs). NEBs figure prominently during the perinatal period when they are postulated to be involved in physiological adaptation to air breathing. Previous studies have documented hyperplasia of NEBs in cystic fibrosis (CF) lungs and increased neuropeptide (bombesin) content produced by these cells, possibly secondary to chronic hypoxia related to CF lung disease. However, little is known about the role of NEBs in the pathogenesis of CF lung disease. In the present study, using a panel of cystic fibrosis transmembrane conductance regulator (CFTR)-specific antibodies and confocal microscopy in combination with RT-PCR, we demonstrate expression of CFTR message and protein in NEB cells of rabbit neonatal lungs. NEB cells expressed CFTR along with neuroendocrine markers. Confocal microscopy established apical membrane localization of the CFTR protein in NEB cells. Cl(-) conductances corresponding to functional CFTR were demonstrated in NEB cells in a fresh lung slice preparation. Our findings suggest that NEBs, and related neuroendocrine mechanisms, likely play a role in the pathogenesis of CF lung disease, including the early stages before establishment of chronic infection and chronic lung disease.     

Social neuroendocrinology

In this paper we provide a critical review of research concerned with social/environmental mechanisms that modulate human neuroendocrine function. We survey research in four behavioral systems that have been shaped through evolution: competition, partnering, sex, and pregnancy/parenting. Generally, behavioral neuroendocrine research examines how hormones affect behavior. Instead, we focus on approaches that emphasize the effects of behavioral states on hormones (i.e., the “reverse relationship”), and their functional significance. We focus on androgens and estrogens because of their relevance to sexually selected traits. We conclude that the body of research employing a reversed or bidirectional perspective has an incomplete foundation: participants are mainly heterosexual men, and the functionality of induced shifts in neuroendocrine factors is generally unknown. This area of research is in its infancy, and opportunities abound for developing and testing intriguing research questions.     

Neuroendocrine properties of macrophage migration inhibitory factor (MIF)

The cytokine macrophage migration inhibitory factor (MIF) is produced by neuroendocrine and immune tissues and possesses several features that allow it to be characterized as a neuroendocrine mediator. Its pro-inflammatory action and its pathogenic role in inflammatory diseases, such as septic shock, arthritis and other diseases, have clearly been demonstrated and may be based in part on neuroendocrine mechanisms. Macrophage migration inhibitory factor possesses glucocorticoid-antagonist properties within the immune system and participates in the regulation of several endocrine circuits. This review summarizes the current state of MIF research and focuses on MIF expression and function in nervous and endocrine tissues.     

Experimentally induced variation in neuroendocrine processes affects male reproductive behaviour,sperm characteristics and social interactions

While extensive research has focused on how social interactions evolve, the fitness consequences of the neuroendocrine mechanisms underlying these interactions have rarely been documented, especially in the wild. Here, we measure how the neuroendocrine mechanisms underlying male behaviour affect mating success and sperm competition in the ocellated wrasse (Symphodus ocellatus). In this species, males exhibit three alternative reproductive types. “Nesting males” provide parental care, defend territories and form cooperative associations with unrelated “satellites,” who cheat by sneaking fertilizations but help by reducing sperm competition from “sneakers” who do not cooperate or provide care. To measure the fitness consequences of the mechanisms underlying these social interactions, we used “phenotypic engineering” that involved administering an androgen receptor antagonist (flutamide) to wild, free‐living fish. Nesting males treated with flutamide shifted their aggression from sneakers to satellite males and experienced decreased submissiveness by sneaker males (which correlated with decreased nesting male mating success). The preoptic area (POA), a region controlling male reproductive behaviours, exhibited dramatic down‐regulation of androgen receptor (AR) and vasotocin 1a receptor (V1aR) mRNA following experimental manipulation of androgen signalling. We did not find a direct effect of the manipulation on male mating success, paternity or larval production. However, variation in neuroendocrine mechanisms generated by the experimental manipulation was significantly correlated with changes in behaviour and mating success: V1aR expression was negatively correlated with satellite‐directed aggression, and expression of its ligand arginine vasotocin (AVT) was positively correlated with courtship and mating success, thus revealing the potential for sexual selection on these mechanisms.     

Priming in exocytosis: attaining fusion-competence after vesicle docking

Membrane contact established by tethering or docking mechanisms is not a sufficient condition for membrane fusion. In neural and neuroendocrine cells, only a small fraction of secretory vesicles docked at the plasma membrane are fusion-competent and undergo rapid ATP-independent fusion in response to Ca(2+) elevations. Additional biochemical events termed 'priming' are essential to render vesicles competent for Ca(2+)-triggered fusion. The priming of vesicles is ATP-dependent and a number of ATP-dependent priming reactions have been characterized in permeable neuroendocrine cells. These involve NSF-mediated priming of SNARE protein complexes, the ATP-dependent synthesis of phosphoinositides, and protein kinase-mediated protein phosphorylation. In addition, munc13 is an important protein involved in priming synaptic vesicles. An emphasis in this review is on recent work indicating that priming events identified in the pathways of regulated exocytosis share many features with pre-fusion processes characterized in constitutive fusion pathways.     

Novel splice variants of rat CaV2.1 that lack much of the synaptic protein interaction site are expressed in neuroendocrine cells

Voltage-gated Ca(2+) channels are responsible for the activation of the Ca(2+) influx that triggers exocytotic secretion. The synaptic protein interaction (synprint) site found in the II-III loop of Ca(V)2.1 and Ca(V)2.2 mediates a physical association with synaptic proteins that may be crucial for fast neurotransmission and axonal targeting. We report here the use of nested PCR to identify two novel splice variants of rat Ca(V)2.1 that lack much of the synprint site. Furthermore, we compare immunofluorescence data derived from antibodies directed against sequences in the Ca(V)2.1 synprint site and carboxyl terminus to show that channel variants lacking a portion of the synprint site are expressed in two types of neuroendocrine cells. Immunofluorescence data also suggest that such variants are properly targeted to neuroendocrine terminals. When expressed in a mammalian cell line, both splice variants yielded Ca(2+) currents, but the variant containing the larger of the two deletions displayed a reduced current density and a marked shift in the voltage dependence of inactivation. These results have important implications for Ca(V)2.1 function and for the mechanisms of Ca(V)2.1 targeting in neurons and neuroendocrine cells.     

A neuroendocrine model for prolactin as the key mediator of seasonal breeding in birds under long- and short-day photoperiods

Seasonal breeding is associated with sequential increases in plasma luteinizing hormone (LH) and prolactin in the short-day breeding emu, and in long-day breeding birds that terminate breeding by the development of reproductive photorefractoriness. A model of the avian neuroendocrine photoperiodic reproductive response is proposed, incorporating a role for prolactin, to account for neuroendocrine mechanisms controlling both long- and short-day breeding. The breeding season terminates after circulating concentrations of prolactin increase above a critical threshold to depress gonadotropin releasing hormone (GnRH) neuronal and gonadotrope (LH) activity. Subsequently, photorefractoriness develops for prolactin secretion and for LH secretion, independently of high plasma prolactin. The breeding season in the emu is advanced compared with long-day breeders, because after photorefractiness for both LH and prolactin secretion is dissipated, plasma concentrations of both hormones increase to maximum values while days are still short.     

Hsp70 in the atrial neuroendocrine units of the snail, Achatina fulica

Heat shock proteins (Hsps) are evolutionary conserved peptides well known as molecular chaperones and stress proteins. Elevated levels of extracellular Hsps in blood plasma have been observed during the stress responses and some diseases. Information on the cellular sources of extracellular Hsps and mechanisms regulating their release is still scanty. Here we showed the presence and localization of Hsp70 in the neuroendocrine system in the atrium of the snail, Achatina fulica. The occurrence of the peptide in snail atrium lysate was detected by Western blot analysis. Immunoperoxidase and immunogold staining demonstrated that Hsp70-immunoreactivity is mainly confined to the peculiar atrial neuroendocrine units which are formed by nerve fibers tightly contacted with large granular cells. Immunolabelling intensity differed in morphologically distinct types of secretory granules in the granular cells. The pictures of exocytosis of Hsp70-immunolabeled granules from the granular cells were observed. In nerve bundles, axon profiles with Hsp70-immunoreactive and those with non-immunoreactive neurosecretory granules were found. In addition, Hsp70-like material was also revealed in the granules of glia-interstitial cells that accompanied nerve fibers. Our findings provide an immuno-morphological basis for a role of Hsp70 in the functioning of the neuroendocrine system in the snail heart, and show that the atrial granular cells are a probable source of extracellular Hsp70 in the snail hemolymph.     

Interpretation of the post-surgical Somatostatin Receptor Scintigram of a Primary Neuroendocrine Tumor of the Thymus: a case report and literature review

A case of a thymic neuroendocrine tumor and the interpretation problems in a post-surgical Somatostatin Receptor Scintigraphy are presented. In a 53-year-old man with superior vena cava obstruction syndrome an atypical carcinoid of the thymus (neuroendocrine carcinoma of intermediate grade 2), was found at surgery.During his first year of follow-up a Somatostatin Receptor Scintigraphy was recommended. An area of abnormal concentration of the radiopharmaceutical was revealed in the mediastinum at this time.A thorough understanding of the mechanisms of the radiopharmaceutical uptake and of the various clinical settings in which uptake can occur are essential for a proper evaluation of the scintigraphic findings and result in the optimal use of this valuable modality.The literature review provides an overview of this rare type of tumor and insight into the clinical significance of Somatostatin Receptor Scintigraphy.     

Brain glucose-sensing mechanisms: ubiquitous silencing by aglycemia vs. hypothalamic neuroendocrine responses

Interest in brain glucose-sensing mechanisms is motivated by two distinct neuronal responses to changes in glucose concentrations. One mechanism is global and ubiquitous in response to profound hypoglycemia, whereas the other mechanism is largely confined to specific hypothalamic neurons that respond to changes in glucose concentrations in the physiological range. Although both mechanisms use intracellular metabolism as an indicator of extracellular glucose concentration, the two mechanisms differ in key respects. Global hyperpolarization (inhibition) in response to 0 mM glucose can be reversed by pyruvate, implying that the reduction in ATP levels acting through ATP-dependent potassium (K-ATP) channels is the key metabolic signal for the global silencing in response to 0 mM glucose. In contrast, neuroendocrine hypothalamic responses in glucoresponsive and glucose-sensitive neurons (either excitation or inhibition, respectively) to physiological changes in glucose concentration appear to depend on glucokinase; neuroendocrine responses also depend on K-ATP channels, although the role of ATP itself is less clear. Lactate can substitute for glucose to produce these neuroendocrine effects, but pyruvate cannot, implying that NADH (possibly leading to anaplerotic production of malonyl-CoA) is a key metabolic signal for effects of glucose on glucoresponsive and glucose-sensitive hypothalamic neurons.