Serotonin and Dopamine Mimic Glucose-Induced Reinforcement in C. elegans: Potential Role of NSM Neurons and the Serotonin Subtype 4 Receptor

Food produces powerful reinforcement that can lead to overconsumption and likely contributes to the obesity epidemic. The present studies examined molecular mechanisms mediating food-induced reinforcement in the model system C. elegans. After a 1-h training session during which food (bacteria) is paired with the odorant butanone, odor preference for butanone robustly increased. Glucose mimicked this effect of bacteria. Glucose-induced odor preference was enhanced similarly by prior food withdrawal or blocking glucose metabolism in the presence of food. Food- and glucose-induced odor preference was mimicked by serotonin signaling through the serotonin type-4 (5-HT4) receptor. Dopamine (thought to act primarily through a D1-like receptor) facilitated, whereas the D2 agonist bromocriptine blocked, food- and glucose-induced odor preference. Furthermore, prior food withdrawal similarly influenced reward produced by serotonin, dopamine, or food, implying post-synaptic enhancement of sensitivity to serotonin and dopamine. These results suggest that glucose metabolism plays a key role in mediating both food-induced reinforcement and enhancement of that reinforcement by prior food withdrawal and implicate serotonergic signaling through 5-HT4 receptor in the re-enforcing properties of food.

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How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

Biochemical Society Transactions ◽

10.1042/bst20190944 ◽

2020 ◽

Vol 48 (3) ◽

pp. 1019-1034 ◽

Cited By ~ 1

Author(s):

Rachel M. Woodhouse ◽

Alyson Ashe

Keyword(s):

Histone Modifications ◽

Molecular Mechanisms ◽

Epigenetic Inheritance ◽

Nematode Caenorhabditis Elegans ◽

Histone Methyltransferases ◽

Transgenerational Epigenetic Inheritance ◽

C Elegans ◽

Recent Developments ◽

Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

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CREB mediates the C. elegans dauer polyphenism through direct and cell-autonomous regulation of TGF-β expression

PLoS Genetics ◽

10.1371/journal.pgen.1009678 ◽

2021 ◽

Vol 17 (7) ◽

pp. e1009678

Author(s):

JiSoo Park ◽

Hyekyoung Oh ◽

Do-Young Kim ◽

YongJin Cheon ◽

Yeon-Ji Park ◽

...

Keyword(s):

Developmental Plasticity ◽

Molecular Mechanisms ◽

Environmental Changes ◽

Marker Gene ◽

Camp Response Element Binding ◽

Camp Response Element ◽

Developmental Programs ◽

C Elegans ◽

Element Binding Protein

Animals can adapt to dynamic environmental conditions by modulating their developmental programs. Understanding the genetic architecture and molecular mechanisms underlying developmental plasticity in response to changing environments is an important and emerging area of research. Here, we show a novel role of cAMP response element binding protein (CREB)-encoding crh-1 gene in developmental polyphenism of C. elegans. Under conditions that promote normal development in wild-type animals, crh-1 mutants inappropriately form transient pre-dauer (L2d) larva and express the L2d marker gene. L2d formation in crh-1 mutants is specifically induced by the ascaroside pheromone ascr#5 (asc-ωC3; C3), and crh-1 functions autonomously in the ascr#5-sensing ASI neurons to inhibit L2d formation. Moreover, we find that CRH-1 directly binds upstream of the daf-7 TGF-β locus and promotes its expression in the ASI neurons. Taken together, these results provide new insight into how animals alter their developmental programs in response to environmental changes.

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Prediabetes linked to excess glucagon in transgenic mice with pancreatic active AKT1

Journal of Endocrinology ◽

10.1530/joe-15-0288 ◽

2015 ◽

Vol 228 (1) ◽

pp. 49-59

Author(s):

Toya M Albury-Warren ◽

Veethika Pandey ◽

Lina P Spinel ◽

Michal M Masternak ◽

Deborah A Altomare

Keyword(s):

Glucose Metabolism ◽

Molecular Mechanisms ◽

Inferior Vena ◽

Vena Cava ◽

Insulin Injection ◽

Hepatic Insulin Resistance ◽

Insulin Resistant ◽

Potential Association ◽

Cell Growth And Proliferation

Protein kinase B/AKT has three isoforms (AKT1–3) and is renowned for its central role in the regulation of cell growth and proliferation, due to its constitutive activation in various cancers. AKT2, which is highly expressed in insulin-responsive tissues, has been identified as a primary regulator of glucose metabolism as Akt2 knockout mice (Akt2−/−) are glucose-intolerant and insulin-resistant. However, the role of AKT1 in glucose metabolism is not as clearly defined. We previously showed that mice with myristoylated Akt1 (AKT1Myr) expressed through a bicistronic Pdx1-TetA and TetO-MyrAkt1 system were susceptible to islet cell carcinomas, and in this study we characterized an early onset, prediabetic phenotype. Beginning at weaning (3 weeks of age), the glucose-intolerant AKT1Myr mice exhibited non-fasted hyperglycemia, which progressed to fasted hyperglycemia by 5 months of age. The glucose intolerance was attributed to a fasted hyperglucagonemia, and hepatic insulin resistance detectable by reduced phosphorylation of the insulin receptor following insulin injection into the inferior vena cava. In contrast, treatment with doxycycline diet to turn off the transgene caused attenuation of the non-fasted and fasted hyperglycemia, thus affirming AKT1 hyperactivation as the trigger. Collectively, this model highlights a novel glucagon-mediated mechanism by which AKT1 hyperactivation affects glucose homeostasis and provides an avenue to better delineate the molecular mechanisms responsible for diabetes mellitus and the potential association with pancreatic cancer.

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A multicellular rosette-mediated collective dendrite extension

eLife ◽

10.7554/elife.38065 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 10

Author(s):

Li Fan ◽

Ismar Kovacevic ◽

Maxwell G Heiman ◽

Zhirong Bao

Keyword(s):

Adhesion Molecules ◽

Molecular Mechanisms ◽

Neural Circuits ◽

Sensory Nerve ◽

Neuronal Cell ◽

Sensory Organ ◽

Neurite Extension ◽

C Elegans ◽

Neuronal Cell Bodies

Coordination of neurite morphogenesis with surrounding tissues is crucial to the establishment of neural circuits, but the underlying cellular and molecular mechanisms remain poorly understood. We show that neurons in a C. elegans sensory organ, called the amphid, undergo a collective dendrite extension to form the sensory nerve. The amphid neurons first assemble into a multicellular rosette. The vertex of the rosette, which becomes the dendrite tips, is attached to the anteriorly migrating epidermis and carried to the sensory depression, extruding the dendrites away from the neuronal cell bodies. Multiple adhesion molecules including DYF-7, SAX-7, HMR-1 and DLG-1 function redundantly in rosette-to-epidermis attachment. PAR-6 is localized to the rosette vertex and dendrite tips, and promotes DYF-7 localization and dendrite extension. Our results suggest a collective mechanism of neurite extension that is distinct from the classical pioneer-follower model and highlight the role of mechanical cues from surrounding tissues in shaping neurites.

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A multicellular rosette-mediated collective dendrite extension

10.1101/303503 ◽

2018 ◽

Cited By ~ 2

Author(s):

Li Fan ◽

Ismar Kovacevic ◽

Maxwell Heiman ◽

Zhirong Bao

Keyword(s):

Adhesion Molecules ◽

Molecular Mechanisms ◽

Neural Circuits ◽

Sensory Nerve ◽

Neuronal Cell ◽

Sensory Organ ◽

Neurite Extension ◽

C Elegans ◽

Neuronal Cell Bodies

Coordination of neurite morphogenesis with surrounding tissues is crucial to the establishment of neural circuits, but the underlying cellular and molecular mechanisms remain poorly understood. We show that neurons in a C. elegans sensory organ, called the amphid, undergo a collective dendrite extension to initiate formation of the sensory nerve. The amphid neurons first assemble into a multicellular rosette. The vertex of the rosette, which becomes the dendrite tips, is attached to the anteriorly migrating epidermis and carried to the sensory depression, extruding the dendrites away from the neuronal cell bodies. Multiple adhesion molecules including DYF-7, SAX-7, HMR-1 and DLG-1 function redundantly in rosette-to-epidermis attachment. PAR-6 is localized to the rosette vertex and dendrite tips, and promotes DYF-7 localization and dendrite extension. Our results suggest a collective mechanism of neurite extension that is distinct from the classical pioneer-follower model and highlight the role of mechanical cues from surrounding tissues in shaping neurites.

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Addressing the Role of Obesity in Endometrial Cancer Risk, Prevention, and Treatment

Journal of Clinical Oncology ◽

10.1200/jco.2016.69.4638 ◽

2016 ◽

Vol 34 (35) ◽

pp. 4225-4230 ◽

Cited By ~ 109

Author(s):

Michaela A. Onstad ◽

Rosemarie E. Schmandt ◽

Karen H. Lu

Keyword(s):

Endometrial Cancer ◽

Cancer Risk ◽

Molecular Mechanisms ◽

Risk Prevention ◽

Endometrial Cancer Risk ◽

Obesity Epidemic ◽

Incidence And Mortality ◽

Cancer Types ◽

The Impact

In sharp contrast to many other cancer types, the incidence and mortality of endometrial cancer continue to grow. This unfortunate trend is, in no small part, a result of the worldwide obesity epidemic. More than half of endometrial cancers are currently attributable to obesity, which is recognized as an independent risk factor for this disease. In this review, we identify the molecular mechanisms by which obesity and adipose tissue contribute to the pathogenesis of endometrial cancer. We further discuss the impact of obesity on the clinical management of the disease and examine the development of rational behavioral and pharmaceutical interventions aimed at reducing endometrial cancer risk, improving cancer outcomes, and preserving fertility in an increasingly younger population of patients with endometrial cancer.

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CREB mediates the C. elegans dauer polyphenism through direct and cell-autonomous regulation of TGF-β expression

10.1101/2020.08.14.250498 ◽

2020 ◽

Author(s):

Jisoo Park ◽

Hyekyung Oh ◽

Do-Young Kim ◽

YongJin Cheon ◽

Yeon-Ji Park ◽

...

Keyword(s):

Developmental Plasticity ◽

Molecular Mechanisms ◽

Environmental Changes ◽

Marker Gene ◽

Camp Response Element Binding ◽

Camp Response Element ◽

Developmental Programs ◽

C Elegans ◽

Element Binding Protein

AbstractAnimals can adapt to dynamic environmental conditions by modulating their developmental programs. Understanding the genetic architecture and molecular mechanisms underlying developmental plasticity in response to changing environments is an important and emerging area of research. Here, we show a novel role of cAMP response element binding protein (CREB)-encoding crh-1 gene in developmental polyphenism of C. elegans. Under conditions that promote normal development in wild-type animals, crh-1 mutants inappropriately form transient pre-dauer (L2d) larva and express the L2d marker gene. L2d formation in crh-1 mutants is specifically induced by the ascaroside pheromone ascr#5 (asc-ωC3; C3), and crh-1 functions autonomously in the ascr#5-sensing ASI neurons to inhibit L2d formation. Moreover, we find that CRH-1 directly binds upstream of the daf-7 TGF-β locus and promotes its expression in the ASI neurons. Taken together, these results provide new insight into how animals alter their developmental programs in response to environmental changes.

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Increasing Notch signaling antagonizes PRC2-mediated silencing to promote reprograming of germ cells into neurons

eLife ◽

10.7554/elife.15477 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 21

Author(s):

Stefanie Seelk ◽

Irene Adrian-Kalchhauser ◽

Balázs Hargitai ◽

Martina Hajduskova ◽

Silvia Gutnik ◽

...

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Germ Cells ◽

Molecular Mechanisms ◽

Notch Signaling Pathway ◽

Germline Stem Cells ◽

Polycomb Repressive Complex 2 ◽

C Elegans ◽

Functional Studies

Cell-fate reprograming is at the heart of development, yet very little is known about the molecular mechanisms promoting or inhibiting reprograming in intact organisms. In the C. elegans germline, reprograming germ cells into somatic cells requires chromatin perturbation. Here, we describe that such reprograming is facilitated by GLP-1/Notch signaling pathway. This is surprising, since this pathway is best known for maintaining undifferentiated germline stem cells/progenitors. Through a combination of genetics, tissue-specific transcriptome analysis, and functional studies of candidate genes, we uncovered a possible explanation for this unexpected role of GLP-1/Notch. We propose that GLP-1/Notch promotes reprograming by activating specific genes, silenced by the Polycomb repressive complex 2 (PRC2), and identify the conserved histone demethylase UTX-1 as a crucial GLP-1/Notch target facilitating reprograming. These findings have wide implications, ranging from development to diseases associated with abnormal Notch signaling.

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Preconditioning of Caenorhabditis elegans to Anoxic Insult by Inactivation of Cholinergic, GABAergic, and Muscle Activity

10.1101/2020.08.28.266890 ◽

2020 ◽

Author(s):

Heather L. Bennett ◽

Patrick D. McClanahan ◽

Christopher Fang-Yen ◽

Robert G. Kalb

Keyword(s):

Nervous System ◽

Chloride Channels ◽

Body Wall ◽

Molecular Mechanisms ◽

Oxygen Deprivation ◽

C Elegans ◽

Cell Dysfunction ◽

Sublethal Stress ◽

Body Wall Muscles

AbstractFor most metazoans, oxygen deprivation leads to cell dysfunction and if severe, death. Sublethal stress prior to a hypoxic or anoxic insult (“preconditioning”) can protect cells from subsequent oxygen deprivation. The molecular mechanisms by which sublethal stress can buffer against a subsequent toxic insult and the role of the nervous system in the response are not well understood. We studied the role of neuronal activity preconditioning to oxygen deprivation in C. elegans. Animals expressing the histamine gated chloride channels (HisCl1) in select cell populations were used to temporally and spatially inactivate the nervous system or tissue prior to an anoxic insult. We find that inactivation of the nervous system for 3 hours prior to the insult confers resistance to a 48-hour anoxic insult in 4th-stage larval animals. Experiments show that this resistance can be attributed to loss of activity in cholinergic and GABAergic neurons as well as in body wall muscles. These observations indicate that the nervous system activity can mediate the organism’s response to anoxia.

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Neurocircuits integrating hormone and nutrient signaling in control of glucose metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00685.2007 ◽

2008 ◽

Vol 294 (5) ◽

pp. E810-E816 ◽

Cited By ~ 22

Author(s):

Eva Rother ◽

A. Christine Könner ◽

Jens C. Brüning

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Glucose Metabolism ◽

Molecular Mechanisms ◽

Pivotal Role ◽

Energy Regulation ◽

Peripheral Organs ◽

Nutrient Signaling ◽

The Central Nervous System

As obesity, diabetes, and associated comorbidities are on a constant rise, large efforts have been put into better understanding the cellular and molecular mechanisms by which nutrients and metabolic signals influence central and peripheral energy regulation. For decades, peripheral organs as a source and a target of such cues have been the focus of study. Their ability to integrate metabolic signals is essential for balanced energy and glucose metabolism. Only recently has the pivotal role of the central nervous system in the control of fuel partitioning been recognized. The rapidly expanding knowledge on the elucidation of molecular mechanisms and neuronal circuits involved is the focus of this review.

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