Pituitary melanotrope cells of Xenopus laevis are of neural ridge origin and do not require induction by the infundibulum.

Classical studies in amphibians have concluded that the endocrine pituitary and pars intermedia are derived from epithelial buccal epidermis and do not require the infundibulum for their induction. These studies also assumed that the pituitary is not subsequently determined by infundibular induction. Our extirpation, auto-transplantation and immunohistochemical studies with Xenopus laevis were initiated to investigate early presumptive pituitary development. These studies were conducted especially with reference to the pars intermedia melanotrope cell's induction, and its production and release of α-melanophore stimulating hormone (α-MSH) from the precursor protein proopiomelanocortin (POMC). Auto-transplantation studies demonstrated that the pituitary POMC-producing cells are determined at a stage prior to pituitary-infundibular contact. The results of experiments involving the extirpation of the presumptive infundibulum also indicated that the infundibulum is not essential for the differentiation of POMC-producing cells. We also demonstrated that early pituitary development involves adherence to the prechiasmatic area of the diencephalon with the pituitary placode growing in a posterior direction toward the infundibulum where contact occurs at Xenopus stage 39/40. Overall, our studies provide a model for early tissue relations among presumptive pituitary, suprachiasmatic nucleus, pars tuberalis and infundibulum during neurulation and later neural tube stages of development. It is hypothesized that the overlying chiasmatic area suppresses pituitary differentiation.

The role of brain-derived neurotrophic factor in the regulation of cell growth and gene expression in melanotrope cells of Xenopus laevis.

Brain-derived neurotrophic factor (BDNF) is, despite its name, also found outside the central nervous system (CNS), but the functional significance of this observation is largely unknown. This review concerns the expression of BDNF in the pituitary gland. While the presence of the neurotrophin in the mammalian pituitary gland is well documented its functional significance remains obscure. Studies on the pars intermedia of the pituitary of the amphibian Xenopus laevis have shown that BDNF is produced by the neuroendocrine melanotrope cells, its expression is physiologically regulated, and the melanotrope cells themselves express receptors for the neurotrophin. The neurotrophin has been shown to act as an autocrine factor on the melanotrope to promote cell growth and regulate gene expression. In doing so BDNF supports the physiological function of the cell to produce and release α-melanophore-stimulating hormone for the purpose of adjusting the animal's skin color to that of its background.

Gene expression profiling of pituitary melanotrope cells during their physiological activation.

The pituitary melanotrope cells of the amphibian Xenopus laevis are responsible for the production of the pigment-dispersing peptide α-melanophore-stimulating hormone, which allows the animal to adapt its skin color to its environment. During adaptation to a dark background the melanotrope cells undergo remarkable changes characterized by dramatic increases in cell size and secretory activity. In this study we performed microarray mRNA expression profiling to identify genes important to melanotrope activation and growth. We show a strong increase in the expression of the immediate early gene (IEG) c-Fos and of the brain-derived neurotrophic factor gene (BDNF). Furthermore, we demonstrate the involvement of another IEG in the adaptation process, Nur77, and conclude from in vitro experiments that the expression of both c-Fos and Nur77 are partially regulated by the adenylyl cyclase system and calcium ions. In addition, we found a steady up-regulation of Ras-like product during the adaptation process, possibly evoked by BDNF/TrkB signaling. Finally, the gene encoding the 105-kDa heat shock protein HSPh1 was transiently up-regulated in the course of black-background adaptation and a gene product homologous to ferritin (ferritin-like product) was >100-fold up-regulated in fully black-adapted animals. We suggest that these latter two genes are induced in response to cellular stress and that they may be involved in changing the mode of mRNA translation required to meet the increased demand for de novo protein synthesis. Together, our results show that microarray analysis is a valuable approach to identify the genes responsible for generating coordinated responses in physiologically activated cells.

ERK-regulated double cortin-like kinase (DCLK)-short phosphorylation and nuclear translocation stimulate POMC gene expression in endocrine melanotrope cells.

We tested whether double cortin-like kinase-short (DCLK-short), a microtubule-associated Ser/Thr kinase predominantly expressed in the brain, is downstream of the ERK signaling pathway and is involved in proopiomelanocortin gene (POMC) expression in endocrine pituitary melanotrope cells of Xenopus laevis. Melanotropes form a well-established model to study physiological aspects of neuroendocrine plasticity. The amphibian X. laevis adapts its skin color to the background light intensity by the release of α-MSH from the melanotrope cell. In frogs on a white background, melanotropes are inactive but they are activated during adaptation to a black background. Our results show that melanotrope activation is associated with an increase in DCLK-short mRNA and with phosphorylation of DCLK-short at serine at position 30 (Ser-30). Upon cell activation phosphorylated Ser-30-DCLK-short was translocated from the cytoplasm into the nucleus, and the ERK blocker U0126 inhibited this process. The mutation of Ser-30 to alanine also inhibited the translocation and reduced POMC expression, whereas overexpression stimulated POMC expression. This is the first demonstration of DCLK-short in a native endocrine cell. We conclude that DCLK-short is physiologically regulated at both the level of its gene expression and protein phosphorylation and that the kinase is effectively regulating POMC gene expression upon its ERK-mediated phosphorylation.

Analysis of the melanotrope cell neuroendocrine interface in two amphibian species, Rana ridibunda and Xenopus laevis: a celebration of 35 years of collaborative research.

This review gives an overview of the functioning of the hypothalamo-hypophyseal neuroendocrine interface in the pituitary neurointermediate lobe, as it relates to melanotrope cell function in two amphibian species, Rana ridibunda and Xenopus laevis. It primarily but not exclusively concerns the work of two collaborating laboratories, the Laboratory for Molecular and Cellular Neuroendocrinology (University of Rouen, France) and the Department of Cellular Animal Physiology (Radboud University Nijmegen, The Netherlands). In the course of this review it will become apparent that Rana and Xenopus have, for the most part, developed the same or similar strategies to regulate the release of α-melanophore-stimulating hormone (α-MSH). The review concludes by highlighting the molecular and cellular mechanisms utilized by thyrotropin-releasing hormone (TRH) to activate Rana melanotrope cells and the function of autocrine brain-derived neurotrophic factor (BDNF) in the regulation of Xenopus melanotrope cell function.

Brain-derived neurotrophic factor stimulates growth of pituitary melanotrope cells in an autocrine way.

Brain-derived neurotrophic factor (BDNF) is expressed in the mammalian pituitary gland, in both the anterior and intermediate lobes, where its functional significance is unknown. Melanotrope cells in the intermediate pituitary lobe of the amphibian Xenopus laevis also produce BDNF, which co-exists in secretory granules with α-melanophore-stimulating hormone (α-MSH), a peptide that causes pigment dispersion in dermal melanophores during adaptation of the toad to a dark background. Xenopus melanotropes are highly plastic, undergoing very strong growth to support the high biosynthesis and release of α-MSH in black-adapted animals. In this study we have tested our hypothesis that this enhanced growth of the melanotrope is maintained by autocrine release of BDNF. Furthermore, since the extracellular-regulated kinase (ERK) pathway is a major component of BDNF signaling in neuronal plasticity, we investigated its involvement in melanotrope cell growth. For these purposes melanotropes were treated for 3 days in vitro, with either an anti-BDNF serum or a recombinant tropomyosin-receptor kinase B (TrkB) receptor fragment to eliminate released BDNF, or with the ERK inhibitor U0126. We also applied a novel inhibitor of the TrkB receptor, cyclotraxin-B, to test this receptor's involvement in melanotrope cell growth regulation. All treatments markedly reduced melanotrope cell growth. Therefore, we conclude that autocrine release of BDNF and subsequent TrkB-dependent ERK-mediated signaling is important for melanotrope cell growth during its physiologically induced activation.

Plasticity of melanotrope cell regulations in Xenopus laevis.

This review focuses on the plasticity of the regulation of a particular neuroendocrine transducer cell, the melanotrope cell in the pituitary pars intermedia of the amphibian Xenopus laevis. This cell type is a suitable model to study the relationship between various external regulatory inputs and the secretion of an adaptive endocrine message, in this case the release of α-melanophore-stimulating hormone, which activates skin melanophores to darken when the animal is placed on a dark background. Information about the environmental conditions is processed by various brain centres, in the hypothalamus and elsewhere, that eventually control the activity of the melanotrope cell regarding hormone production and secretion. The review discusses the roles of these hypothalamic and extrahypothalamic nuclei, their neurochemical messengers acting on the melanotrope, and the external stimuli they mediate to control melanotrope cell functioning.

BDNF stimulates Ca2+ oscillation frequency in melanotrope cells of Xenopus laevis: contribution of IP3-receptor-mediated release of intracellular Ca2+ to gene expression.

Pituitary melanotrope cells of the amphibian Xenopus laevis are neuroendocrine cells regulating the animal's skin color adaptation through secretion of α-melanophore-stimulating hormone (α-MSH). To fulfill this function optimally, the melanotrope cell undergoes plastic changes in structure and secretory activity in response to changed background light conditions. Xenopus melanotrope cells display Ca(2+) oscillations that are thought to drive α-MSH secretion and gene expression. They also produce brain-derived neurotrophic factor (BDNF), which stimulates in an autocrine way the biosynthesis of the α-MSH precursor, pro-opiomelanocortin (POMC). We have used this physiological adaptation mechanism as a model to investigate the role of BDNF in the regulation of Ca(2+) kinetics and Ca(2+)-dependent gene expression. By dynamic video imaging of isolated cultured melanotropes we demonstrated that BDNF caused a dose-dependent increase in Ca(2+) oscillation frequency up to 64.7±2.3% of control level. BDNF also induced a transient Ca(2+) peak in Ca(2+)-free medium, which was absent when calcium stores were blocked by thapsigargin and 2-aminoethoxydiphenyl borate, indicating that BDNF stimulates acute release of Ca(2+) from IP(3)-sensitive intracellular Ca(2+) stores. Moreover, we show that thapsigargin inhibits the expression of BDNF transcript IV (by 61.1±28.8%) but does not affect POMC transcript. We conclude that BDNF mobilizes Ca(2+) from IP(3)-sensitive intracellular Ca(2+) stores and propose the possibility that the resulting Ca(2+) oscillations selectively stimulate expression of the BDNF gene.

A developmental analysis of periodic albinism in the amphibian Xenopus laevis.

The periodic albino of Xenopus laevis displays a transitory presence of black melanin pigment in the embryo but looses this during tadpole development. This mutation, involving a recessive allele, affects melanogenesis in dermal melanophore pigment cells. It has been suggested that the mutation is intrinsic to the melanophore cell itself or, alternatively, reflects malfunction in the neuroendocrine system that regulates melanophore cell function. This latter system, involving pituitary melanotrope cells which produces alpha-melanophore stimulating hormone (alpha-MSH), is responsible for stimulating the production and dispersion of melanin pigment in dermal melanophores. The purpose of the present study was to determine to which degree the albinism is intrinsic to the melanophore or involves neuroendocrine malfunction. Experiments involved transplantation of presumptive melanophores from wild-type to albino embryos, and vice versa, immunocytochemical analysis of the albino neuroendocrine system and the creation of wild-type/albino parabiotic animals to determine if the neuroendocrine system of the albino can support melanotrope cell function. We show that the albino has a functional neuroendocrine system and conclude that the defect in the albino primarily affects the melanophore cell, possibly rendering it incapable of responding to alpha-MSH. It is also apparent from our results that in later stages of development the cellular environment of the melanotrope cell does become important to its development, but the nature of the critical cellular factors involved remains to be determined.

About a snail, a toad, and rodents: animal models for adaptation research.

Neural adaptation mechanisms have many similarities throughout the animal kingdom, enabling to study fundamentals of human adaptation in selected animal models with experimental approaches that are impossible to apply in man. This will be illustrated by reviewing research on three of such animal models, viz. (1) the egg-laying behavior of a snail, Lymnaea stagnalis: how one neuron type controls behavior, (2) adaptation to the ambient light condition by a toad, Xenopus laevis: how a neuroendocrine cell integrates complex external and neural inputs, and (3) stress, feeding, and depression in rodents: how a neuronal network co-ordinates different but related complex behaviors. Special attention is being paid to the actions of neurochemical messengers, such as neuropeptide Y, urocortin 1, and brain-derived neurotrophic factor. While awaiting new technological developments to study the living human brain at the cellular and molecular levels, continuing progress in the insight in the functioning of human adaptation mechanisms may be expected from neuroendocrine research using invertebrate and vertebrate animal models.

TRH acts as a multifunctional hypophysiotropic factor in vertebrates.

Thyrotropin-releasing hormone (TRH) is the first hypothalamic hypophysiotropic neuropeptide whose sequence has been chemically characterized. The primary structure of TRH (pGlu-His-Pro-NH(2)) has been fully conserved across the vertebrate phylum. TRH is generated from a large precursor protein that contains multiple repeats of the TRH progenitor tetrapeptide Gln-His-Pro-Gly. In all tetrapods, TRH-expressing neurons located in the hypothalamus project towards the external zone of the median eminence while in teleosts they directly innervate the pars distalis of the pituitary. In addition, in frogs and teleosts, a bundle of TRH-containing fibers terminate in the neurointermediate lobe of the pituitary gland. Although TRH was originally named for its ability to trigger the release of thyroid-stimulating hormone (TSH) in mammals, it later became apparent that it exerts multiple, species-dependent hypophysiotropic activities. Thus, in fish TRH stimulates growth hormone (GH) and prolactin (PRL) release but does not affect TSH secretion. In amphibians, TRH is a marginal stimulator of TSH release in adult frogs, not in tadpoles, and a major releasing factor for GH and PRL. In birds, TRH triggers TSH and GH secretion. In mammals, TRH stimulates TSH, GH and PRL release. In fish and amphibians, TRH is also a very potent stimulator of alpha-melanocyte-stimulating hormone release. Because the intermediate lobe of the pituitary of amphibians is composed by a single type of hormone-producing cells, the melanotrope cells, it is a suitable model in which to investigate the mechanism of action of TRH at the cellular and molecular level. The occurrence of large amounts of TRH in the frog skin and high concentrations of TRH in frog plasma suggests that, in amphibians, skin-derived TRH may exert hypophysiotropic functions.

Regulation of proopiomelanocortin gene expression: an overview of the signaling cascades, transcription factors, and responsive elements involved.

Pituitary melanotroph and corticotroph cells produce and secrete peptides from the multifunctional precursor protein proopiomelanocortin (POMC). Stimulation of the secretory activity of both cell types involves production of cyclic 3'5'-adenosine monophosphate (cAMP) and increases in the concentration of intracellular Ca(2+). The increase in secretory activity is accompanied by enhanced expression of the POMC gene. Surprisingly, the POMC promoter lacks both cAMP-responsive elements and Ca(2+)-responsive elements through which the cAMP and Ca(2+) signals could, in a relatively direct way, act on POMC gene expression. It is thus apparent that other, more indirect, mechanisms have evolved to utilize cAMP and Ca(2+) signaling cascades to regulate POMC expression. This review gives an overview of the complex pathways and events that lead to the regulation of POMC gene expression in corticotrophs and melanotrophs. Another major site for POMC production is in hypothalamic neurons of the arcuate nucleus. In these neurons expression of the POMC gene relies on enhancer regions and responsive elements that differ from those utilized in the pituitary gland. In this review some attention will be given to progress made in unraveling the regulatory strategies acting on POMC expression in hypothalamic neurons. It is clear that the complexities of the promoter/enhancer structure of the POMC gene contribute to the versatility of this gene in participating in complex adaptation processes.

A Self-Study Tutorial using the Allen Brain Explorer and Brain Atlas to Teach Concepts of Mammalian Neuroanatomy and Brain Function.

The Allen Brain Atlas is a repository of neuroanatomical data concerning the mouse brain. The core of the database is a Nissl-stained reference atlas of the brain accompanied by in situ hybridization data for essentially the entire mouse genome. This database is freely available at the Allen Institute for Brain Science website, as is an innovative tool to explore the database, the Brain Explorer. This tool is downloaded and installed on your own computer. I have developed a self-study tutorial, "Explorations with the Allen Brain Explorer", which uses the Brain Explorer and the Brain Atlas to teach fundamentals of mammalian neuroanatomy and brain function. In this tutorial background information and step-by-step exercises on the use of the Brain Explorer are given using PowerPoint as a platform. To do the tutorial both the PowerPoint and the Brain Explorer are opened on the computer and the students switch from one program to the other as they go, in a step-wise fashion, through the various exercises. There are two main groups of exercises, titled "The Basics" and "Explorations", with both groups accessed from a PowerPoint "Start Menu" by clicking on dynamic links to the appropriate exercises. Most exercises have a number of dynamic links to PowerPoint slides where background information for the exercises is given or the neuroanatomical data collected from the Brain Atlas is discussed.

Differential neuroendocrine expression of multiple brain-derived neurotrophic factor transcripts.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin with important growth-promoting properties. We report here the first characterization of a BDNF gene in an amphibian, Xenopus laevis, and demonstrate that environmental factors can activate this gene in a promoter-specific fashion. The Xenopus BDNF gene contains six promoter-specific 5'-exons and one 3'-protein-encoding exon. We examined the expression of promoter-specific transcripts in Xenopus neuroendocrine melanotrope cells. These cells make a good model to study how environmental factors control gene expression. In animals placed on a black background melanotrope cells more actively produce and release alphaMSH than in animals on a white background. BDNF is cosequestered and coreleased with alphaMSH and stimulates biosynthesis of proopiomelanocortin (POMC), the precursor protein for alphaMSH. Our analysis of the expression of the BDNF transcripts revealed that there is differential use of some BDNF promoters in melanotrope cells, depending on the adaptation state of the frog. During black-background adaptation, stimulation of expression of BDNF transcript IV preceded that of the POMC transcript, suggesting the BDNF gene is an effector gene for POMC expression. The possible mechanisms regulating expression of the various transcripts are discussed on the basis of the potential calcium- and cAMP-responsive elements in the promoter region of exon IV. Finally, we show that the upstream open reading frames of BDNF transcripts I and IV markedly decrease BDNF translation efficiency, giving the first indication for a functional role of untranslated BDNF exons.

Intracellular signal transduction by the extracellular calcium-sensing receptor of Xenopus melanotrope cells.

The extracellular calcium-sensing receptor (CaR) is expressed in various types of endocrine pituitary cell, but the intracellular mechanism this G protein-coupled receptor uses in these cells is not known. In the present study we investigated possible intracellular signal transduction pathway(s) utilized by the CaR of the endocrine melanotrope cells in the intermediate pituitary lobe of the South African-clawed toad Xenopus laevis. For this purpose, the effects of various pharmacological agents on CaR-evoked secretion of radiolabeled secretory peptides from cultured melanotrope cells were assessed. CaR-evoked secretion, induced by the potent CaR agonist L-phenylalanine (L-Phe), could not be inhibited by cholera toxin, nor by NPC-15437 and PMA, indicating that neither G(s)/PKA nor G(q)/PKC pathways are involved. However, pertussis toxin (G(i/o) protein inhibitor), genistein (inhibitor of PTKs), wortmannin/LY-294002 (PI3-K inhibitor) and U-0126 (inhibitor of extracellular signal-regulated kinase, ERK) all substantially inhibited CaR-evoked secretion, indicating that the Xenopus melanotrope cell possesses a PI3-K/MAPK system that plays some role in CaR-signaling. Since no direct effect of L-Phe on ERK phosphorylation could be shown it is concluded that CaR must act primarily through another, still unknown, signaling pathway in Xenopus melanotropes. Our results indicate that the PI3-K/MAPK system has a facilitating effect on CaR-induced secretion, possibly by sensitizing the CaR.

Pituitary adenylate cyclase-activating polypeptide regulates brain-derived neurotrophic factor exon IV expression through the VPAC1 receptor in the amphibian melanotrope cell.

In mammals, pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors PAC1-R, VPAC1-R, and VPAC2-R play a role in various physiological processes, including proopiomelanocortin (POMC) and brain-derived neurotrophic factor (BDNF) gene expression. We have previously found that PACAP stimulates POMC gene expression, POMC biosynthesis, and alpha-MSH secretion in the melanotrope cell of the amphibian Xenopus laevis. This cell hormonally controls the process of skin color adaptation to background illumination. Here, we have tested the hypothesis that PACAP is involved in the regulation of Xenopus melanotrope cell activity during background adaptation and that part of this regulation is through the control of the expression of autocrine acting BDNF. Using quantitative RT-PCR, we have identified the Xenopus PACAP receptor, VPAC1-R, and show that this receptor in the melanotrope cell is under strong control of the background light condition, whereas expression of PAC1-R was absent from these cells. Moreover, we reveal by quantitative immunocytochemistry that the neural pituitary lobe of white-background adapted frogs possesses a much higher PACAP content than the neural lobe of black-background adapted frogs, providing evidence that PACAP produced in the hypothalamic magnocellular nucleus plays an important role in regulating the activity of Xenopus melanotrope cells during background adaptation. Finally, an in vitro study demonstrates that PACAP stimulates the expression of BDNF transcript IV.

Calcium channel kinetics of melanotrope cells in Xenopus laevis depend on environmental stimulation.

We have tested the hypothesis that the type and kinetics of voltage-activated Ca(2+) channels in a neuroendocrine cell depend on the cell's long-term external input. For this purpose, the presence and kinetics of both low (LVA) and high-voltage-activated (HVA) L-type Ca(2+) channels have been assessed in melanotrope pituitary cells of the amphibian Xenopus laevis. The secretory activity of this cell type can readily be manipulated in vivo by changing the animal's environmental light condition, from a black to a white background. We here show that, compared to white background-adapted Xenopus, melanotropes from black background-adapted frogs have (1) a much larger size, as revealed by their 2.5 times larger membrane capacitance (P<0.001), (2) a 2 times higher HVA current density (P<0.05), (3) a clearly smaller Ca(2+)-dependent inactivation (10%; P<0.05), (4) L-type channels with 5 times slower activation and inactivation kinetics (P<0.05), and (5) slower kinetics of L-type channels that become faster and more similar to those in white-background adapted cells when the intracellular Ca(2+)-buffering capacity is reduced. Furthermore, white-adapted melanotropes possess LVA-type Ca(2+) channels, which are lacking from cells from black-adapted animals. The melanotrope calmodulin mRNA level does not differ between the two adaptation states. These results indicate that HVA L-type channel kinetics differ in relation to environmentally induced changes in cellular secretory state, probably mediated via intracellular Ca(2+)-buffering, whereas the occurrence of LVA Ca(2+) channels may depend on environmentally controlled channel gene expression.

Expression and physiological regulation of BDNF receptors in the neuroendocrine melanotrope cell of Xenopus laevis.

Brain-derived neurotrophic factor (BDNF) and alpha-melanophore-stimulating hormone (alpha-MSH) are co-sequestered in secretory granules in melanotrope cells of the pituitary pars intermedia of the amphibian Xenopus laevis. alpha-MSH is responsible for pigment dispersion in dermal melanophores during the process of black-background adaptation. BDNF-production in melanotrope cells is increased by placing animals on a black background, and BDNF acts as an autocrine stimulatory factor on the melanotrope cells. However, the repertoire of possible neurotrophin receptors of the melanotrope is unknown. In this study we have established the expression of full length TrkB (TrkB.FL), truncated TrkB (TrkB.T) and p75(NTR) receptors in the Xenopus neurointermediate lobe by RT-PCR. In situ hybridization reveals the presence of TrkB.FL mRNA and p75(NTR) mRNA in melanotrope cells. Quantitative RT-PCR shows that in animals on a black background the amounts of TrkB.T and p75(NTR) mRNA are about three times higher than in white background-adapted animals. We suggest that the amount of p75(NTR) sets the sensitivity of the melanotrope cells for the stimulatory action of BDNF during physiological adaptation to background light intensity.

Actions of PACAP and VIP on melanotrope cells of Xenopus laevis.

The neuropeptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are implicated in the regulation of gene expression and hormone secretion in mammalian melanotrope cells and a mammalian pro-opiomelanocortin (POMC)-producing tumor cell line, but the physiological relevance of this regulation is elusive. The purpose of the present study was to establish if these peptides affect biosynthetic and secretory processes in a well-established physiological model for endocrine cell functioning, the pituitary melanotrope cells of the amphibian Xenopus laevis, which hormonally control the process of skin color adaptation to background illumination. We show that both PACAP and VIP are capable of stimulating the secretory process of the Xenopus melanotrope cell. As the peptides are equipotent, they may exert their actions via a VPAC receptor. Moreover, PACAP stimulated POMC biosynthesis and POMC gene expression. Strong anti-PACAP immunoreactivity was found in the pituitary pars nervosa (PN), suggesting that this neurohemal organ is a source of neurohormonal PACAP action on the melanotropes in the intermediate pituitary. We propose that the PACAP/VIP family of peptides has a physiological function in regulating Xenopus melanotrope cell activity during the process of skin color adaptation.

Plasticity in the melanotrope neuroendocrine interface of Xenopus laevis.

Melanotrope cells of the amphibian pituitary pars intermedia produce alpha-melanophore-stimulating hormone (alpha-MSH), a peptide which causes skin darkening during adaptation to a dark background. The secretory activity of the melanotrope of the South African clawed toad Xenopus laevis is regulated by multiple factors, both classical neurotransmitters and neuropeptides from the brain. This review concerns the plasticity displayed in this intermediate lobe neuroendocrine interface during physiological adaptation to the environment. The plasticity includes dramatic morphological plasticity in both pre- and post-synaptic elements of the interface. Inhibitory neurons in the suprachiasmatic nucleus, designated suprachiasmatic melanotrope-inhibiting neurons (SMINs), possess more and larger synapses on the melanotrope cells in white than in black-background adapted animals; in the latter animals the melanotropes are larger and produce more proopiomelanocortin (POMC), the precursor of alpha-MSH. On a white background, pre-synaptic SMIN plasticity is reflected by a higher expression of inhibitory neuropeptide Y (NPY) and is closely associated with postsynaptic melanotrope plasticity, namely a higher expression of the NPY Y1 receptor. Interestingly, melanotrope cells in such animals also display higher expression of the receptors for thyrotropin-releasing hormone (TRH) and urocortin 1, two neuropeptides that stimulate alpha-MSH secretion. Possibly, in white-adapted animals melanotropes are sensitized to neuropeptide stimulation so that, when the toad moves to a black background, they can immediately initiate alpha-MSH secretion to achieve rapid adaptation to the new background condition. The melanotrope cell also produces brain-derived neurotrophic factor (BDNF), which is co-sequestered with alpha-MSH in secretory granules within the cells. The neurotrophin seems to control melanotrope cell plasticity in an autocrine way and we speculate that it may also control presynaptic SMIN plasticity.