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Lef1-dependent hypothalamic neurogenesis inhibits anxiety.
Xie Y, Kaufmann D, Moulton MJ, Panahi S, Gaynes JA, Watters HN, Zhou D, Xue HH, Fung CM, Levine EM, Letsou A, Brennan KC, Dorsky RI
(2017) PLoS Biol 15: e2002257
MeSH Terms: Animals, Anxiety, Behavior, Animal, Biomarkers, Drosophila Proteins, Drosophila melanogaster, Female, Gene Expression Regulation, Genes, Reporter, Humans, Hypothalamus, Lymphoid Enhancer-Binding Factor 1, Male, Mice, Knockout, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Neurogenesis, Neurons, Species Specificity, Transcription Factors, Zebrafish, Zebrafish Proteins
Show Abstract · Added February 14, 2018
While innate behaviors are conserved throughout the animal kingdom, it is unknown whether common signaling pathways regulate the development of neuronal populations mediating these behaviors in diverse organisms. Here, we demonstrate that the Wnt/ß-catenin effector Lef1 is required for the differentiation of anxiolytic hypothalamic neurons in zebrafish and mice, although the identity of Lef1-dependent genes and neurons differ between these 2 species. We further show that zebrafish and Drosophila have common Lef1-dependent gene expression in their respective neuroendocrine organs, consistent with a conserved pathway that has diverged in the mouse. Finally, orthologs of Lef1-dependent genes from both zebrafish and mouse show highly correlated hypothalamic expression in marmosets and humans, suggesting co-regulation of 2 parallel anxiolytic pathways in primates. These findings demonstrate that during evolution, a transcription factor can act through multiple mechanisms to generate a common behavioral output, and that Lef1 regulates circuit development that is fundamentally important for mediating anxiety in a wide variety of animal species.
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23 MeSH Terms
Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation.
Dean ED, Li M, Prasad N, Wisniewski SN, Von Deylen A, Spaeth J, Maddison L, Botros A, Sedgeman LR, Bozadjieva N, Ilkayeva O, Coldren A, Poffenberger G, Shostak A, Semich MC, Aamodt KI, Phillips N, Yan H, Bernal-Mizrachi E, Corbin JD, Vickers KC, Levy SE, Dai C, Newgard C, Gu W, Stein R, Chen W, Powers AC
(2017) Cell Metab 25: 1362-1373.e5
MeSH Terms: Amino Acid Transport Systems, Neutral, Animals, Cell Proliferation, Glucagon, Glutamine, Liver, Mice, Mice, Knockout, Signal Transduction, Zebrafish, Zebrafish Proteins
Show Abstract · Added September 21, 2018
Decreasing glucagon action lowers the blood glucose and may be useful therapeutically for diabetes. However, interrupted glucagon signaling leads to α cell proliferation. To identify postulated hepatic-derived circulating factor(s) responsible for α cell proliferation, we used transcriptomics/proteomics/metabolomics in three models of interrupted glucagon signaling and found that proliferation of mouse, zebrafish, and human α cells was mTOR and FoxP transcription factor dependent. Changes in hepatic amino acid (AA) catabolism gene expression predicted the observed increase in circulating AAs. Mimicking these AA levels stimulated α cell proliferation in a newly developed in vitro assay with L-glutamine being a critical AA. α cell expression of the AA transporter Slc38a5 was markedly increased in mice with interrupted glucagon signaling and played a role in α cell proliferation. These results indicate a hepatic α islet cell axis where glucagon regulates serum AA availability and AAs, especially L-glutamine, regulate α cell proliferation and mass via mTOR-dependent nutrient sensing.
Copyright © 2017 Elsevier Inc. All rights reserved.
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MeSH Terms
A role for Gle1, a regulator of DEAD-box RNA helicases, at centrosomes and basal bodies.
Jao LE, Akef A, Wente SR
(2017) Mol Biol Cell 28: 120-127
MeSH Terms: Active Transport, Cell Nucleus, Adenosine Triphosphatases, Antigens, Basal Bodies, Centrosome, DEAD-box RNA Helicases, Nuclear Pore, Nuclear Pore Complex Proteins, Nucleocytoplasmic Transport Proteins, Protein Binding, RNA Transport, RNA, Messenger, RNA-Binding Proteins, Zebrafish Proteins
Show Abstract · Added April 14, 2017
Control of organellar assembly and function is critical to eukaryotic homeostasis and survival. Gle1 is a highly conserved regulator of RNA-dependent DEAD-box ATPase proteins, with critical roles in both mRNA export and translation. In addition to its well-defined interaction with nuclear pore complexes, here we find that Gle1 is enriched at the centrosome and basal body. Gle1 assembles into the toroid-shaped pericentriolar material around the mother centriole. Reduced Gle1 levels are correlated with decreased pericentrin localization at the centrosome and microtubule organization defects. Of importance, these alterations in centrosome integrity do not result from loss of mRNA export. Examination of the Kupffer's vesicle in Gle1-depleted zebrafish revealed compromised ciliary beating and developmental defects. We propose that Gle1 assembly into the pericentriolar material positions the DEAD-box protein regulator to function in localized mRNA metabolism required for proper centrosome function.
© 2017 Jao et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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14 MeSH Terms
Expression of Cataract-linked γ-Crystallin Variants in Zebrafish Reveals a Proteostasis Network That Senses Protein Stability.
Wu SY, Zou P, Fuller AW, Mishra S, Wang Z, Schey KL, Mchaourab HS
(2016) J Biol Chem 291: 25387-25397
MeSH Terms: Animals, Cataract, Lens Capsule, Crystalline, Mice, Mutation, Protein Aggregates, Zebrafish, Zebrafish Proteins, alpha-Crystallin A Chain, gamma-Crystallins
Show Abstract · Added May 6, 2017
The refractivity and transparency of the ocular lens is dependent on the stability and solubility of the crystallins in the fiber cells. A number of mutations of lens crystallins have been associated with dominant cataracts in humans and mice. Of particular interest were γB- and γD-crystallin mutants linked to dominant cataracts in mouse models. Although thermodynamically destabilized and aggregation-prone, these mutants were found to have weak affinity to the resident chaperone α-crystallin in vitro To better understand the mechanism of the cataract phenotype, we transgenically expressed different γD-crystallin mutants in the zebrafish lens and observed a range of lens defects that arise primarily from the aggregation of the mutant proteins. Unlike mouse models, a strong correlation was observed between the severity and penetrance of the phenotype and the level of destabilization of the mutant. We interpret this result to reflect the presence of a proteostasis network that can "sense" protein stability. In the more destabilized mutants, the capacity of this network is overwhelmed, leading to the observed increase in phenotypic penetrance. Overexpression of αA-crystallin had no significant effects on the penetrance of lens defects, suggesting that its chaperone capacity is not limiting. Although consistent with the prevailing hypothesis that a chaperone network is required for lens transparency, our results suggest that αA-crystallin may not be efficient to inhibit aggregation of lens γ-crystallin. Furthermore, our work implicates additional inputs/factors in this underlying proteostasis network and demonstrates the utility of zebrafish as a platform to delineate mechanisms of cataract.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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10 MeSH Terms
A transcription factor network controls cell migration and fate decisions in the developing zebrafish pineal complex.
Khuansuwan S, Clanton JA, Dean BJ, Patton JG, Gamse JT
(2016) Development 143: 2641-50
MeSH Terms: Animals, Body Patterning, Cell Count, Cell Lineage, Cell Movement, Gene Dosage, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Habenula, Larva, Mosaicism, Mutation, Neurons, Pineal Gland, Retinal Rod Photoreceptor Cells, Transcription Factors, Zebrafish, Zebrafish Proteins
Show Abstract · Added August 4, 2017
The zebrafish pineal complex consists of four cell types (rod and cone photoreceptors, projection neurons and parapineal neurons) that are derived from a single pineal complex anlage. After specification, parapineal neurons migrate unilaterally away from the rest of the pineal complex whereas rods, cones and projection neurons are non-migratory. The transcription factor Tbx2b is important for both the correct number and migration of parapineal neurons. We find that two additional transcription factors, Flh and Nr2e3, negatively regulate parapineal formation. Flh induces non-migratory neuron fates and limits the extent of parapineal specification, in part by activation of Nr2e3 expression. Tbx2b is positively regulated by Flh, but opposes Flh action during specification of parapineal neurons. Loss of parapineal neuron specification in Tbx2b-deficient embryos can be partially rescued by loss of Nr2e3 or Flh function; however, parapineal migration absolutely requires Tbx2b activity. We conclude that cell specification and migration in the pineal complex are regulated by a network of at least three transcription factors.
© 2016. Published by The Company of Biologists Ltd.
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18 MeSH Terms
Cyp27c1 Red-Shifts the Spectral Sensitivity of Photoreceptors by Converting Vitamin A1 into A2.
Enright JM, Toomey MB, Sato SY, Temple SE, Allen JR, Fujiwara R, Kramlinger VM, Nagy LD, Johnson KM, Xiao Y, How MJ, Johnson SL, Roberts NW, Kefalov VJ, Guengerich FP, Corbo JC
(2015) Curr Biol 25: 3048-57
MeSH Terms: Amphibian Proteins, Animals, Cytochrome P-450 Enzyme System, Infrared Rays, Photoreceptor Cells, Vertebrate, Rana catesbeiana, Transcriptome, Visual Perception, Vitamin A, Zebrafish, Zebrafish Proteins
Show Abstract · Added March 14, 2018
Some vertebrate species have evolved means of extending their visual sensitivity beyond the range of human vision. One mechanism of enhancing sensitivity to long-wavelength light is to replace the 11-cis retinal chromophore in photopigments with 11-cis 3,4-didehydroretinal. Despite over a century of research on this topic, the enzymatic basis of this perceptual switch remains unknown. Here, we show that a cytochrome P450 family member, Cyp27c1, mediates this switch by converting vitamin A1 (the precursor of 11-cis retinal) into vitamin A2 (the precursor of 11-cis 3,4-didehydroretinal). Knockout of cyp27c1 in zebrafish abrogates production of vitamin A2, eliminating the animal's ability to red-shift its photoreceptor spectral sensitivity and reducing its ability to see and respond to near-infrared light. Thus, the expression of a single enzyme mediates dynamic spectral tuning of the entire visual system by controlling the balance of vitamin A1 and A2 in the eye.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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11 MeSH Terms
FGF1 Mediates Overnutrition-Induced Compensatory β-Cell Differentiation.
Li M, Page-McCaw P, Chen W
(2016) Diabetes 65: 96-109
MeSH Terms: Animals, Animals, Genetically Modified, Cell Differentiation, Cell Line, Tumor, Endoplasmic Reticulum Stress, Fibroblast Growth Factor 1, Flow Cytometry, Humans, Insulin-Secreting Cells, Overnutrition, RNA, Messenger, Rats, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Zebrafish, Zebrafish Proteins
Show Abstract · Added February 15, 2016
Increased insulin demand resulting from insulin resistance and/or overnutrition induces a compensatory increase in β-cell mass. The physiological factors responsible for the compensation have not been fully characterized. In zebrafish, overnutrition rapidly induces compensatory β-cell differentiation through triggering the release of a paracrine signal from persistently activated β-cells. We identified Fgf1 signaling as a key component of the overnutrition-induced β-cell differentiation signal in a small molecule screen. Fgf1 was confirmed as the overnutrition-induced β-cell differentiation signal, as inactivation of fgf1 abolished the compensatory β-cell differentiation. Furthermore, expression of human FGF1 solely in β-cells in fgf1(-/-) animals rescued the compensatory response, indicating that β-cells can be the source of FGF1. Additionally, constitutive secretion of FGF1 with an exogenous signal peptide increased β-cell number in the absence of overnutrition. These results demonstrate that fgf1 is necessary and FGF1 expression in β-cells is sufficient for the compensatory β-cell differentiation. We further show that FGF1 is secreted during prolonged activation of cultured mammalian β-cells and that endoplasmic reticulum stress acts upstream of FGF1 release. Thus, the recently discovered antidiabetes function of FGF1 may act partially through increasing β-cell differentiation.
© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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16 MeSH Terms
The RNA Binding Protein Igf2bp1 Is Required for Zebrafish RGC Axon Outgrowth In Vivo.
Gaynes JA, Otsuna H, Campbell DS, Manfredi JP, Levine EM, Chien CB
(2015) PLoS One 10: e0134751
MeSH Terms: Actins, Animals, Axons, Gene Knockdown Techniques, RNA-Binding Proteins, Retinal Ganglion Cells, Zebrafish, Zebrafish Proteins
Show Abstract · Added November 2, 2015
Attractive growth cone turning requires Igf2bp1-dependent local translation of β-actin mRNA in response to external cues in vitro. While in vivo studies have shown that Igf2bp1 is required for cell migration and axon terminal branching, a requirement for Igf2bp1 function during axon outgrowth has not been demonstrated. Using a timelapse assay in the zebrafish retinotectal system, we demonstrate that the β-actin 3'UTR is sufficient to target local translation of the photoconvertible fluorescent protein Kaede in growth cones of pathfinding retinal ganglion cells (RGCs) in vivo. Igf2bp1 knockdown reduced RGC axonal outgrowth and tectal coverage and retinal cell survival. RGC-specific expression of a phosphomimetic Igf2bp1 reduced the density of axonal projections in the optic tract while sparing RGCs, demonstrating for the first time that Igf2bp1 is required during axon outgrowth in vivo. Therefore, regulation of local translation mediated by Igf2bp proteins may be required at all stages of axon development.
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8 MeSH Terms
An in vivo chemical genetic screen identifies phosphodiesterase 4 as a pharmacological target for hedgehog signaling inhibition.
Williams CH, Hempel JE, Hao J, Frist AY, Williams MM, Fleming JT, Sulikowski GA, Cooper MK, Chiang C, Hong CC
(2015) Cell Rep 11: 43-50
MeSH Terms: Animals, Cyclic AMP-Dependent Protein Kinases, Cyclic Nucleotide Phosphodiesterases, Type 4, Hedgehog Proteins, Phosphodiesterase 4 Inhibitors, Pyrimidinones, Receptors, G-Protein-Coupled, Signal Transduction, Small Molecule Libraries, Smoothened Receptor, Thiophenes, Transcriptional Activation, Zebrafish, Zebrafish Proteins
Show Abstract · Added April 5, 2015
Hedgehog (Hh) signaling plays an integral role in vertebrate development, and its dysregulation has been accepted widely as a driver of numerous malignancies. While a variety of small molecules target Smoothened (Smo) as a strategy for Hh inhibition, Smo gain-of-function mutations have limited their clinical implementation. Modulation of targets downstream of Smo could define a paradigm for treatment of Hh-dependent cancers. Here, we describe eggmanone, a small molecule identified from a chemical genetic zebrafish screen, which induced an Hh-null phenotype. Eggmanone exerts its Hh-inhibitory effects through selective antagonism of phosphodiesterase 4 (PDE4), leading to protein kinase A activation and subsequent Hh blockade. Our study implicates PDE4 as a target for Hh inhibition, suggests an improved strategy for Hh-dependent cancer therapy, and identifies a unique probe of downstream-of-Smo Hh modulation.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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14 MeSH Terms
Circadian modulation of dopamine levels and dopaminergic neuron development contributes to attention deficiency and hyperactive behavior.
Huang J, Zhong Z, Wang M, Chen X, Tan Y, Zhang S, He W, He X, Huang G, Lu H, Wu P, Che Y, Yan YL, Postlethwait JH, Chen W, Wang H
(2015) J Neurosci 35: 2572-87
MeSH Terms: Animals, Animals, Genetically Modified, Attention Deficit Disorder with Hyperactivity, Avoidance Learning, Behavior, Animal, Circadian Rhythm, Dopamine, Dopaminergic Neurons, Impulsive Behavior, Larva, Mice, Motor Activity, NIH 3T3 Cells, Period Circadian Proteins, Tyrosine 3-Monooxygenase, Zebrafish, Zebrafish Proteins
Show Abstract · Added February 20, 2015
Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in children and adults. While ADHD patients often display circadian abnormalities, the underlying mechanisms are unclear. Here we found that the zebrafish mutant for the circadian gene period1b (per1b) displays hyperactive, impulsive-like, and attention deficit-like behaviors and low levels of dopamine, reminiscent of human ADHD patients. We found that the circadian clock directly regulates dopamine-related genes monoamine oxidase and dopamine β hydroxylase, and acts via genes important for the development or maintenance of dopaminergic neurons to regulate their number and organization in the ventral diencephalic posterior tuberculum. We then found that Per1 knock-out mice also display ADHD-like symptoms and reduced levels of dopamine, thereby showing highly conserved roles of the circadian clock in ADHD. Our studies demonstrate that disruption of a circadian clock gene elicits ADHD-like syndrome. The circadian model for attention deficiency and hyperactive behavior sheds light on ADHD pathogenesis and opens avenues for exploring novel targets for diagnosis and therapy for this common psychiatric disorder.
Copyright © 2015 the authors 0270-6474/15/352572-16$15.00/0.
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17 MeSH Terms