Regulation of the Mouse Ventral Tegmental Area by Melanin-Concentrating Hormone.

Melanin-concentrating hormone (MCH) acts via its sole receptor MCHR1 in rodents and is an important regulator of homeostatic behaviors like feeding, sleep, and mood to impact overall energy balance. The loss of MCH signaling by MCH or MCHR1 deletion produces hyperactive mice with increased energy expenditure, and these effects are consistently associated with a hyperdopaminergic state. We recently showed that MCH suppresses dopamine release in the nucleus accumbens, which principally receives dopaminergic projections from the ventral tegmental area (VTA), but the mechanisms underlying MCH-regulated dopamine release are not clearly defined. MCHR1 expression is widespread and includes dopaminergic VTA cells. However, as the VTA is a neurochemically diverse structure, we assessed Mchr1 gene expression at glutamatergic, GABAergic, and dopaminergic VTA cells and determined if MCH inhibited the activity of VTA cells and/or their local microcircuit. Mchr1 expression was robust in major VTA cell types, including most dopaminergic (78%) or glutamatergic cells (52%) and some GABAergic cells (38%). Interestingly, MCH directly inhibited dopaminergic and GABAergic cells but did not regulate the activity of glutamatergic cells. Rather, MCH produced a delayed increase in excitatory input to dopamine cells and a corresponding decrease in GABAergic input to glutamatergic VTA cells. Our findings suggested that MCH may acutely suppress dopamine release while disinhibiting local glutamatergic signaling to restore dopamine levels. This indicated that the VTA is a target of MCH action, which may provide bidirectional regulation of energy balance.

Heterozygous variants in SIX3 and POU1F1 cause pituitary hormone deficiency in mouse and man.

Congenital hypopituitarism is a genetically heterogeneous condition that is part of a spectrum disorder that can include holoprosencephaly. Heterozygous mutations in SIX3 cause variable holoprosencephaly in humans and mice. We identified two children with neonatal hypopituitarism and thin pituitary stalk who were doubly heterozygous for rare, likely deleterious variants in the transcription factors SIX3 and POU1F1. We used genetically engineered mice to understand the disease pathophysiology. Pou1f1 loss-of-function heterozygotes are unaffected; Six3 heterozygotes have pituitary gland dysmorphology and incompletely ossified palate; and the Six3+/-; Pou1f1+/dw double heterozygote mice have a pronounced phenotype, including pituitary growth through the palate. The interaction of Pou1f1 and Six3 in mice supports the possibility of digenic pituitary disease in children. Disruption of Six3 expression in the oral ectoderm completely ablated anterior pituitary development, and deletion of Six3 in the neural ectoderm blocked the development of the pituitary stalk and both anterior and posterior pituitary lobes. Six3 is required in both oral and neural ectodermal tissues for the activation of signaling pathways and transcription factors necessary for pituitary cell fate. These studies clarify the mechanism of SIX3 action in pituitary development and provide support for a digenic basis for hypopituitarism.

Genetic deciphering of the antagonistic activities of the melanin-concentrating hormone and melanocortin pathways in skin pigmentation.

The genetic origin of human skin pigmentation remains an open question in biology. Several skin disorders and diseases originate from mutations in conserved pigmentation genes, including albinism, vitiligo, and melanoma. Teleosts possess the capacity to modify their pigmentation to adapt to their environmental background to avoid predators. This background adaptation occurs through melanosome aggregation (white background) or dispersion (black background) in melanocytes. These mechanisms are largely regulated by melanin-concentrating hormone (MCH) and α-melanocyte-stimulating hormone (α-MSH), two hypothalamic neuropeptides also involved in mammalian skin pigmentation. Despite evidence that the exogenous application of MCH peptides induces melanosome aggregation, it is not known if the MCH system is physiologically responsible for background adaptation. In zebrafish, we identify that MCH neurons target the pituitary gland-blood vessel portal and that endogenous MCH peptide expression regulates melanin concentration for background adaptation. We demonstrate that this effect is mediated by MCH receptor 2 (Mchr2) but not Mchr1a/b. mchr2 knock-out fish cannot adapt to a white background, providing the first genetic demonstration that MCH signaling is physiologically required to control skin pigmentation. mchr2 phenotype can be rescued in adult fish by knocking-out pomc, the gene coding for the precursor of α-MSH, demonstrating the relevance of the antagonistic activity between MCH and α-MSH in the control of melanosome organization. Interestingly, MCH receptor is also expressed in human melanocytes, thus a similar antagonistic activity regulating skin pigmentation may be conserved during evolution, and the dysregulation of these pathways is significant to our understanding of human skin disorders and cancers.

Molecular codes and in vitro generation of hypocretin and melanin concentrating hormone neurons.

Hypocretin/orexin (HCRT) and melanin concentrating hormone (MCH) neuropeptides are exclusively produced by the lateral hypothalamus and play important roles in sleep, metabolism, reward, and motivation. Loss of HCRT (ligands or receptors) causes the sleep disorder narcolepsy with cataplexy in humans and in animal models. How these neuropeptides are produced and involved in diverse functions remain unknown. Here, we developed methods to sort and purify HCRT and MCH neurons from the mouse late embryonic hypothalamus. RNA sequencing revealed key factors of fate determination for HCRT (Peg3, Ahr1, Six6, Nr2f2, and Prrx1) and MCH (Lmx1, Gbx2, and Peg3) neurons. Loss of Peg3 in mice significantly reduces HCRT and MCH cell numbers, while knock-down of a Peg3 ortholog in zebrafish completely abolishes their expression, resulting in a 2-fold increase in sleep amount. We also found that loss of HCRT neurons in Hcrt-ataxin-3 mice results in a specific 50% decrease in another orexigenic neuropeptide, QRFP, that might explain the metabolic syndrome in narcolepsy. The transcriptome results were used to develop protocols for the production of HCRT and MCH neurons from induced pluripotent stem cells and ascorbic acid was found necessary for HCRT and BMP7 for MCH cell differentiation. Our results provide a platform to understand the development and expression of HCRT and MCH and their multiple functions in health and disease.

Effects of background color and feeding status on the expression of genes associated with body color regulation in the goldfish Carassius auratus.

Alpha-melanocyte-stimulating hormone (α-MSH), a peptide derived from proopiomelanocortin (POMC), and melanin-concentrating hormone (MCH), act as neuromodulators and regulate food intake in vertebrates. In teleosts, these peptides are also involved competitively in body color regulation; α-MSH induces a dark body color, while MCH induces a pale body color. Similarly, members of the growth hormone (GH) family, somatolactin (SL) and prolactin (PRL), which are involved in the regulation of energy metabolism, are also associated with body color regulation in teleosts. Since these hormones are involved in both body color regulation and energy metabolism, it is possible that feeding status can affect body color. Here, we examined the effects of fasting on the response of goldfish body coloration to changes in background color. Goldfish were acclimated for one week in tanks with a white or black background under conditions of periodic feeding or fasting. The results showed that body color and expression levels of pmch1 and pomc were affected by background color, irrespective of feeding status. Expression levels of sla were higher in fish maintained in tanks with a black background than in tanks with a white background, and higher in the fasted fish compared to the fed fish. However, the pattern of slb expression was almost the opposite of that observed in sla expression. The expression levels of gh and prl in the pituitary, and pmch2a and pmch2b in the brain, were not affected by background color. These results suggest that MCH, α-MSH, SLα, and SLß might be involved in body color regulation and that they are affected by background color in goldfish. The results also suggest that feeding status may affect body color regulation via SLα and SLß, although these effects might be limited compared to the effect of background color.

Neural Contributions of the Hypothalamus to Parental Behaviour.

Parental behaviour is a comprehensive set of neural responses to social cues. The neural circuits that govern parental behaviour reside in several putative nuclei in the brain. Melanin concentrating hormone (MCH), a neuromodulator that integrates physiological functions, has been confirmed to be involved in parental behaviour, particularly in crouching behaviour during nursing. Abolishing MCH neurons in innate MCH knockout males promotes infanticide in virgin male mice. To understand the mechanism and function of neural networks underlying parental care and aggression against pups, it is essential to understand the basic organisation and function of the involved nuclei. This review presents newly discovered aspects of neural circuits within the hypothalamus that regulate parental behaviours.

Morphological colour adaptation during development in fish: involvement of growth hormone receptor 1.

Morphological background adaptation is both an endocrine and a nervous response, involving changes in the amount of chromatophores and pigment concentration. However, whether this adaptation takes place at early developmental stages is largely unknown. Somatolactin (Sl) is a pituitary hormone present in fish, which has been associated to skin pigmentation. Moreover, growth hormone receptor type 1 (Ghr1) has been suggested to be the Sl receptor and was associated with background adaptation in adults. In this context, the aim of this work was to evaluate the ontogeny of morphological adaptation to background and the participation of ghr1 in this process. We found in larval stages of the cichlid Cichlasoma dimerus that the number of head melanophores and pituitary cells immunoreactive to Sl was increased in individuals reared with black backgrounds compared with that in fish grown in white tanks. In larval stages of the medaka Oryzias latipes, a similar response was observed, which was altered by ghr1 biallelic mutations using CRISPR/Cas9. Interestingly, melanophore and leucophore numbers were highly associated. Furthermore, we found that somatic growth was reduced in ghr1 biallelic mutant O. latipes, establishing the dual function of this growth hormone receptor. Taken together, these results show that morphological background adaptation is present at early stages during development and that is dependent upon ghr1 during this period.

Sleep-Wake Control by Melanin-Concentrating Hormone (MCH) Neurons: a Review of Recent Findings.

PURPOSE OF THE REVIEW: Melanin-concentrating hormone (MCH)-expressing neurons located in the lateral hypothalamus are considered as an integral component of sleep-wake circuitry. However, the precise role of MCH neurons in sleep-wake regulation has remained unclear, despite several years of research employing a wide range of techniques. We review recent data on this aspect, which are mostly inconsistent, and propose a novel role for MCH neurons in sleep regulation. RECENT FINDINGS: While almost all studies using "gain-of-function" approaches show an increase in rapid eye movement sleep (or paradoxical sleep; PS), loss-of-function approaches have not shown reductions in PS. Similarly, the reported changes in wakefulness or non-rapid eye movement sleep (slow-wave sleep; SWS) with manipulation of the MCH system using conditional genetic methods are inconsistent. Currently available data do not support a role for MCH neurons in spontaneous sleep-wake but imply a crucial role for them in orchestrating sleep-wake responses to changes in external and internal environments.

Expression of Genes Involved in Offensive and Defensive Phenotype Induction in the Pituitary Gland of the Hokkaido Salamander (Hynobius retardatus).

Amphibians exhibit phenotypic plasticity, which allows flexible adaptation to fluctuating environments. Although genes involved in expression of plastic phenotypes have been identified, the endocrine bases of plastic responses are largely unknown. Larvae of the Hokkaido salamander (Hynobius retardatus) plastically display distinct phenotypes, an "offensive phenotype" characterized as larger body with broadened gape and a "defensive phenotype" characterized as enlarged gills and tail and less active behavior, in the presence of prey larval amphibians and predatory larval dragonfly, respectively. In the presence of both prey and predators, the degree of induction of both phenotypes is reduced, suggesting cross-talk between the molecular signaling pathways of these phenotypes. We conducted a transcriptomic analysis to examine how endocrine regulation affects the phenotypic expression by focusing on the pituitary gland. We found that five endocrine genes, i.e., calcitonin related polypeptide alpha (CALCA), growth hormone (GH), neuropeptide B (NPB), parathyroid hormone 2 (PTH2), and prolactin 1 (PRL1), were involved in the expression of both phenotypes. However, we conducted only RNA-seq analysis, and no confirmation of significant up-regulation or down-regulation has been conducted. These results suggest that these genes were up-regulated for induction of the offensive phenotype and down-regulated for induction of the defensive phenotype. Phylogenetic analysis indicated that possible gene duplications of PRL and CALCA have occurred during amphibian evolution. Based on these findings, it is suggested that a trade-off of molecular signaling pathways exists between the two distinct phenotypic expressions. The results also suggest that hormonal-gene duplications might have contributed to the acquisition of phenotypic plasticity in amphibians.

Effects of tank color brightness on the body color, somatic growth, and endocrine systems of rainbow trout Oncorhynchus mykiss.

We investigated the effects of tank brightness on body color, growth, and endocrine systems of rainbow trout (Oncorhynchus mykiss). Five different tank colors that produce varying levels of brightness were used, including black, dark gray [DG], light gray [LG], white, and blue. The fish were reared in these tanks for 59 days under natural photoperiod and water temperature. The body color was affected by tank brightness, such that body color brightness was correlated with tank brightness (white-housed ≥ LG-housed ≥ DG-housed ≥ blue-housed ≥ black-housed). No difference in somatic growth was observed among the fish reared in the five tanks. The mRNA levels of melanin-concentrating hormone (mch1) was higher in white-housed fish than those in the other tanks, and the mRNA levels of proopiomelanocortins (pomc-a and pomc-b) were higher in fish housed in a black tank than those in other tanks. mRNA level of somatolactin, a member of growth hormone family, was higher in black-housed fish than those in white-housed fish. The mRNA levels of mch1 and mch2 in blue-housed fish were similar to those in black-housed fish, while the mRNA levels of pomc-a and pomc-b in blue-housed fish were similar to those in white-housed fish. The current results suggest that tank color is not related to fish growth, therefore any color of conventional rearing tank can be used to grow fish. Moreover, the association between somatolactin with body color changes is suggested in addition to the role of classical MCH and melanophore stimulating hormone derived from POMC.

The effects of chromatic lights on body color and gene expressions of melanin-concentrating hormone and proopiomelanocortin in goldfish (Carassius auratus).

In the present study, the effects of photic environments, such as background color (white and black) and chromatic lights (blue, green, and red), on body color and gene expressions of melanin-concentrating hormone (mch) in the brain and proopiomelanocortin (pomc) in the pituitary, as well as the roles of the eyes and brain as mediators of ambient light to these genes, were examined in goldfish (Carassius auratus). Body color of goldfish exposed to fluorescent light (FL) under white background (WBG) was paler than those under black background (BBG). Gene expression levels for mch and pomc were reciprocally different depending on background color; under WBG, mRNA levels of mch and pomc were high and low, respectively, while under BBG, these levels were reversed. mch and pomc mRNA expressions of the fish exposed to chromatic light from LED were primarily similar to those exposed to FL, while blue light stimulated the expressions of mch and pomc. Ophthalmectomized goldfish exposed to FL or blue light showed minimum expression levels of mch gene, suggesting that eyes are the major mediator of ambient light for mch gene expression. Contrastingly, mRNA expressions of pomc in ophthalmectomized goldfish exposed to FL were different from those of intact goldfish. These results suggest that eyes play a functional role in mediating ambient light to regulate pomc gene expression. Since ophthalmectomy caused an increase in pomc mRNA contents in the fish exposed to blue light, we suggest that the brain is an additional mediator to regulate pomc gene expression.

Characterization and expression of melanin-concentrating hormone (MCH) in common carp (Cyprinus carpio) during fasting and reproductive cycle.

Melanin-concentrating hormone (MCH) was initially known as a regulator of teleost skin color and possesses multiple functions in mammals, such as the regulation of energy balance and reproduction. However, the role of MCH in fish remains unclear. In the present study, a 590 bp cDNA fragment of common carp (Cyprinus carpio) MCH gene was cloned. Amino acid sequence similarities with other teleost ranged from 23 to 93%. The mature MCH peptide (DTMRCMVGRVYRPCWEV) located in the C-terminal region of MCH precursor was 100% identical to that of goldfish, zebrafish, chum salmon, and rainbow trout. Tissue expression profiles showed that MCH mRNA was ubiquitously expressed throughout the brain and peripheral tissues and highly expressed in the brain and pituitary. Within the brain, MCH mRNA was expressed preponderantly in the hypothalamus. MCH mRNA expression in the hypothalamus was increased after feeding, decreased after 3, 5, or 7 days fasting, and increased upon refeeding. These results suggested that MCH might have anorexigenic actions in common carp. Meanwhile, MCH gene expression varied based on reproductive cycle, which might be related to the long-term regulation of MCH in energy balance. In conclusion, our novel finding revealed that MCH was involved in the regulation of appetite and energy balance in common carp.

Melanin-concentrating hormone neurons contribute to dysregulation of rapid eye movement sleep in narcolepsy.

The lateral hypothalamus contains neurons producing orexins that promote wakefulness and suppress REM sleep as well as neurons producing melanin-concentrating hormone (MCH) that likely promote REM sleep. Narcolepsy with cataplexy is caused by selective loss of the orexin neurons, and the MCH neurons appear unaffected. As the orexin and MCH systems exert opposing effects on REM sleep, we hypothesized that imbalance in this REM sleep-regulating system due to activity in the MCH neurons may contribute to the striking REM sleep dysfunction characteristic of narcolepsy. To test this hypothesis, we chemogenetically activated the MCH neurons and pharmacologically blocked MCH signaling in a murine model of narcolepsy and studied the effects on sleep-wake behavior and cataplexy. To chemoactivate MCH neurons, we injected an adeno-associated viral vector containing the hM3Dq stimulatory DREADD into the lateral hypothalamus of orexin null mice that also express Cre recombinase in the MCH neurons (MCH-Cre::OX-KO mice) and into control MCH-Cre mice with normal orexin expression. In both lines of mice, activation of MCH neurons by clozapine-N-oxide (CNO) increased rapid eye movement (REM) sleep without altering other states. In mice lacking orexins, activation of the MCH neurons also increased abnormal intrusions of REM sleep manifest as cataplexy and short latency transitions into REM sleep (SLREM). Conversely, a MCH receptor 1 antagonist, SNAP 94847, almost completely eliminated SLREM and cataplexy in OX-KO mice. These findings affirm that MCH neurons promote REM sleep under normal circumstances, and their activity in mice lacking orexins likely triggers abnormal intrusions of REM sleep into non-REM sleep and wake, resulting in the SLREM and cataplexy characteristic of narcolepsy.

Central CCL2 signaling onto MCH neurons mediates metabolic and behavioral adaptation to inflammation.

Sickness behavior defines the endocrine, autonomic, behavioral, and metabolic responses associated with infection. While inflammatory responses were suggested to be instrumental in the loss of appetite and body weight, the molecular underpinning remains unknown. Here, we show that systemic or central lipopolysaccharide (LPS) injection results in specific hypothalamic changes characterized by a precocious increase in the chemokine ligand 2 (CCL2) followed by an increase in pro-inflammatory cytokines and a decrease in the orexigenic neuropeptide melanin-concentrating hormone (MCH). We therefore hypothesized that CCL2 could be the central relay for the loss in body weight induced by the inflammatory signal LPS. We find that central delivery of CCL2 promotes neuroinflammation and the decrease in MCH and body weight. MCH neurons express CCL2 receptor and respond to CCL2 by decreasing both electrical activity and MCH release. Pharmacological or genetic inhibition of CCL2 signaling opposes the response to LPS at both molecular and physiologic levels. We conclude that CCL2 signaling onto MCH neurons represents a core mechanism that relays peripheral inflammation to sickness behavior.

Evolution of the growth hormone, prolactin, prolactin 2 and somatolactin family.

Growth hormone (GH), prolactin (PRL), prolactin 2 (PRL2) and somatolactin (SL) belong to the same hormone family and have a wide repertoire of effects including development, osmoregulation, metabolism and stimulation of growth. Both the hormone and the receptor family have been proposed to have expanded by gene duplications in early vertebrate evolution. A key question is how hormone-receptor preferences have arisen among the duplicates. The first step to address this is to determine the time window for these duplications. Specifically, we aimed to see if duplications resulted from the two basal vertebrate tetraploidizations (1R and 2R). GH family genes from a broad range of vertebrate genomes were investigated using a combination of sequence-based phylogenetic analyses and comparisons of synteny. We conclude that the PRL and PRL2 genes arose from a common ancestor in 1R/2R, as shown by neighboring gene families. No other gene duplicates were preserved from these tetraploidization events. The ancestral genes that would give rise to GH and PRL/PRL2 arose from an earlier duplication; most likely a local gene duplication as they are syntenic in several species. Likewise, some evidence suggests that SL arose from a local duplication of an ancestral GH/SL gene in the same time window, explaining the lack of similarity in chromosomal neighbors to GH, PRL or PRL2. Thus, the basic triplet of ancestral GH, PRL/PRL2 and SL genes appear to be unexpectedly ancient. Following 1R/2R, only SL was duplicated in the teleost-specific tetraploidization 3R, resulting in SLa and SLb. These time windows contrast with our recent report that the corresponding receptor genes GHR and PRLR arose through a local duplication in jawed vertebrates and that both receptor genes duplicated further in 3R, which reveals a surprising asynchrony in hormone and receptor gene duplications.

Expression of genes for melanotropic peptides and their receptors for morphological color change in goldfish Carassius auratus.

To evaluate the association of the melanotropic peptides and their receptors for morphological color change, we investigated the effects of changes in background color, between white and black, on xanthophore density in the scales and expression levels of genes for hormonal peptides and corresponding receptors (MCH-R2, MC1R, and MC5R) in goldfish (Carassius auratus). The xanthophore density in both dorsal and ventral scales increased after transfer from a white to black background. However, xanthophore density in dorsal scales increased after transfer from a black to white background, and that of ventral scales decreased after transfer from a black to black background, which served as the control. In the white-reared fish, melanin-concentrating hormone (mch) mRNA content in the brain was higher than that in black-reared fish, whereas proopiomelanocortin a (pomc-a) mRNA content in the pituitary was lower than that in the black-reared fish. Agouti-signaling protein (asp) mRNA was detected in the ventral skin but not in the dorsal skin. No difference was observed in the asp mRNA content between fish reared in white or black background, suggesting that ASP might not be associated with background color adaptation. In situ hybridization revealed that both mc1r and mc5r were expressed in the xanthophores in scales. The mRNA content of mc1r in scales did not always follow the background color change, whereas those of mc5r decreased in the white background and increased in the black background, suggesting that mc5r might be a major factor reinforcing the function of MSH in morphological color changes. White backgrounds increased mch mRNA content in the brain, but decreased mch-r2 mRNA content in the scales. These altered expression levels of melanotropin receptors might affect reactivity to melanotropins through long-term adaptation to background color.

Exercise improves growth, alters physiological performance and gene expression in common carp (Cyprinus carpio).

It has been suggested that induced swimming has the potential to improve the growth performance of fish. We tested this hypothesis by measuring growth, metabolic efficiency and physiological capacity of common carp (Cyprinus carpio). Fish were swum at different exercise regimes: 0.0 (control), 1.5 and 2.5 body lengths per second (BL/s) in 1600 L recirculating raceways for 4 weeks. The results showed a significant increase in weight gain, specific growth rate, improved feed conversion efficiency, and a higher hepatosomatic index for 2.5 BL/s exercised fish compared to control. Glycogen, protein and lipid energy stores in hepatic and muscular tissue showed limited differences among experimental groups. Likewise, plasma [Na+], [K+] and [Cl-] remained stable at all swimming regimes. Expression of genes controlling energy metabolism and growth (IGF-I axis, cytochrome oxidase) and stress response (cortisol receptor, heat shock protein 70) revealed clear regulatory roles as the mRNA transcript levels of IGF-I and growth hormone receptors in hepatic tissue were up-regulated in fish exercised for 3-4 weeks at 2.5 BL/s. Oxygen consumption rate and swimming performance (Ucrit) for each experimental group were evaluated in parallel in Blazka-type swim-tunnels (3.9 L) and showed no training effect while prolonged swimming at 1.5 and 2.5 BL/s facilitated ammonia excretion and prevented build-up of plasma ammonia. Overall, these data suggest that sustained exercise at 2.5 BL/s enhanced growth and physiological fitness without compromising energy metabolism or ion-regulation. Our study provides a prospective of implementing exercise as a tool to increase fish production efficiency in commercial aquaculture systems.

NK3R Mediates the EGF-Induced SLα Secretion and mRNA Expression in Grass Carp Pituitary.

Epidermal growth factor (EGF) is a potent regulator of cell function in many cell types. In mammals, the EGF/EGFR system played an important role in both pituitary physiology and pathology. However, it is not clear about the pituitary action of EGF in lower vertebrates. In this study, using grass carp as a model, we found that EGF could stimulate NK3R mRNA and protein expression through pituitary ErbB1 and ErbB2 coupled to MEK/ERK and PI3K/Akt/mTOR pathways. In addition, EGF could also induce pituitary somatolactin α (SLα) secretion and mRNA expression in a dose- and time-dependent manner in vivo and in vitro. The stimulatory actions of EGF on SLα mRNA expression were also mediated by PI3K/Akt/mTOR and MEK/ERK pathways coupled to ErbB1 and ErbB2 activation. Our previous study has reported that neurokinin B (NKB) could also induce SLα secretion and mRNA expression in carp pituitary cells. In the present study, interestingly, we found that EGF could significantly enhance NKB-induced SLα mRNA expression. Further studies found that NK3R antagonist SB222200 could block EGF-induced SLα mRNA expression, indicating an NK3R requirement. Furthermore, cAMP/PKA inhibitors and PLC/PKC inhibitors could both abolish EGF- and EGF+NKB-induced SLα mRNA expression, which further supported that EGF-induced SLα mRNA expression is NK3R dependent.

Characterization and expression analyses of somatolactin-α and -ß genes in rare minnows (Gobiocypris rarus) following waterborne cadmium exposure.

Using reverse transcription-polymerase chain reaction (RT-PCR) and RACE (rapid amplification of cDNA ends), somatolactin-α (rmSLα) and -ß (rmSLß) were identified from the pituitary gland of rare minnows (Gobiocypris rarus). The full-length cDNAs of these two genes were 1288 and 801 bp, encoding prepeptides of 250 and 228 amino acids residues, respectively. rmSLß can be detected in the brain (including the pituitary), ovary, testis, and gill, while rmSLα was mainly expressed in the brain. On the other hand, rmSLα was expressed in all the fetal developmental stages; however, rmSLß can just be detected in the stages since from 14 h post-fertilization (hpf). After exposure to acute waterborne cadmium (Cd), rmSLα was distinctly upregulated in juvenile rare minnows at all detected time points, from 24 to 96 h and 10 days, while rmSLß was significantly altered only in 96 h or 10-day treatment groups. As for adults, acute Cd exposure caused alterations of both rmSLα and rmSLß in the brain (containing the pituitary) at the 24 h; subchronic waterborne Cd treatment led to upregulation of rmSLα, while decrease of mSLß in the brain. Alteration of rmSL transcripts following waterborne Cd exposure further confirmed the endocrine disruption of this heavy metal. Besides, exposure to as low as 5 µg/L Cd caused alteration of rmSLα, which suggested that rmSLα might be a potential biomarker for risk assessment of aquatic Cd.

[Genetic factors in hypopituitarism. The role of transcription factors in pituitary hormone deficiency]. / Genetikai tényezok a hypopituitarismus kialakulásában. A transzkripciós faktorok szerepe az agyalapimirigy-elégtelenség hátterében.

Developmental disorders affecting the hypothalamic-pituitary system can result in pituitary hormone deficiency showing a diverse clinical presentation. A significant majority of these disorders are closely linked to defects in transcription factor genes which play a major role in pituitary development. Those affecting the early phase of organogenesis typically lead to complex conditions affecting the pituitary as well as structures in the central nervous system. Transcription factors involved in the late phase can result in combined but rarely isolated pituitary hormone deficiency without extra-pituitary manifestation. Identifying the defects in these pituitary transcription factor genes may provide a useful tool in predicting disease progression as well as screening family members. Several pituitary transcription factors can be detected in the adult gland as well which is strongly emphasized in the World Health Organization's most recent guideline for pituitary tumor classification. Our review summarizes the current essential knowledge relevant for clinical endocrinologists. Orv Hetil. 2018; 159(7): 278-284.