Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 229

Publication Record

Connections

Phenome-based approach identifies RIC1-linked Mendelian syndrome through zebrafish models, biobank associations and clinical studies.
Unlu G, Qi X, Gamazon ER, Melville DB, Patel N, Rushing AR, Hashem M, Al-Faifi A, Chen R, Li B, Cox NJ, Alkuraya FS, Knapik EW
(2020) Nat Med 26: 98-109
MeSH Terms: Abnormalities, Multiple, Animals, Behavior, Animal, Biological Specimen Banks, Chondrocytes, Disease Models, Animal, Extracellular Matrix, Fibroblasts, Guanine Nucleotide Exchange Factors, Humans, Models, Biological, Musculoskeletal System, Osteogenesis, Phenomics, Phenotype, Procollagen, Protein Transport, Secretory Pathway, Syndrome, Zebrafish, Zebrafish Proteins
Show Abstract · Added January 15, 2020
Discovery of genotype-phenotype relationships remains a major challenge in clinical medicine. Here, we combined three sources of phenotypic data to uncover a new mechanism for rare and common diseases resulting from collagen secretion deficits. Using a zebrafish genetic screen, we identified the ric1 gene as being essential for skeletal biology. Using a gene-based phenome-wide association study (PheWAS) in the EHR-linked BioVU biobank, we show that reduced genetically determined expression of RIC1 is associated with musculoskeletal and dental conditions. Whole-exome sequencing identified individuals homozygous-by-descent for a rare variant in RIC1 and, through a guided clinical re-evaluation, it was discovered that they share signs with the BioVU-associated phenome. We named this new Mendelian syndrome CATIFA (cleft lip, cataract, tooth abnormality, intellectual disability, facial dysmorphism, attention-deficit hyperactivity disorder) and revealed further disease mechanisms. This gene-based, PheWAS-guided approach can accelerate the discovery of clinically relevant disease phenome and associated biological mechanisms.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Developmental regulation of Wnt signaling by Nagk and the UDP-GlcNAc salvage pathway.
Neitzel LR, Spencer ZT, Nayak A, Cselenyi CS, Benchabane H, Youngblood CQ, Zouaoui A, Ng V, Stephens L, Hann T, Patton JG, Robbins D, Ahmed Y, Lee E
(2019) Mech Dev 156: 20-31
MeSH Terms: Animals, Body Patterning, Drosophila, Embryonic Development, Evolution, Molecular, Gene Expression Regulation, Developmental, Glycosylation, Humans, Phosphotransferases (Alcohol Group Acceptor), Wnt Signaling Pathway, Xenopus laevis, Zebrafish
Show Abstract · Added April 10, 2019
In a screen for human kinases that regulate Xenopus laevis embryogenesis, we identified Nagk and other components of the UDP-GlcNAc glycosylation salvage pathway as regulators of anteroposterior patterning and Wnt signaling. We find that the salvage pathway does not affect other major embryonic signaling pathways (Fgf, TGFβ, Notch, or Shh), thereby demonstrating specificity for Wnt signaling. We show that the role of the salvage pathway in Wnt signaling is evolutionarily conserved in zebrafish and Drosophila. Finally, we show that GlcNAc is essential for the growth of intestinal enteroids, which are highly dependent on Wnt signaling for growth and maintenance. We propose that the Wnt pathway is sensitive to alterations in the glycosylation state of a cell and acts as a nutritional sensor in order to couple growth/proliferation with its metabolic status. We also propose that the clinical manifestations observed in congenital disorders of glycosylation (CDG) in humans may be due, in part, to their effects on Wnt signaling during development.
Copyright © 2019 Elsevier B.V. All rights reserved.
0 Communities
1 Members
0 Resources
12 MeSH Terms
GRIK5 Genetically Regulated Expression Associated with Eye and Vascular Phenomes: Discovery through Iteration among Biobanks, Electronic Health Records, and Zebrafish.
Unlu G, Gamazon ER, Qi X, Levic DS, Bastarache L, Denny JC, Roden DM, Mayzus I, Breyer M, Zhong X, Konkashbaev AI, Rzhetsky A, Knapik EW, Cox NJ
(2019) Am J Hum Genet 104: 503-519
MeSH Terms: Animals, Biological Specimen Banks, Electronic Health Records, Embryo, Nonmammalian, Eye Diseases, Gene Expression Regulation, Genotype, Humans, Phenomics, Phenotype, Receptors, Kainic Acid, Vascular Diseases, Zebrafish
Show Abstract · Added March 23, 2019
Although the use of model systems for studying the mechanism of mutations that have a large effect is common, we highlight here the ways that zebrafish-model-system studies of a gene, GRIK5, that contributes to the polygenic liability to develop eye diseases have helped to illuminate a mechanism that implicates vascular biology in eye disease. A gene-expression prediction derived from a reference transcriptome panel applied to BioVU, a large electronic health record (EHR)-linked biobank at Vanderbilt University Medical Center, implicated reduced GRIK5 expression in diverse eye diseases. We tested the function of GRIK5 by depletion of its ortholog in zebrafish, and we observed reduced blood vessel numbers and integrity in the eye and increased vascular permeability. Analyses of EHRs in >2.6 million Vanderbilt subjects revealed significant comorbidity of eye and vascular diseases (relative risks 2-15); this comorbidity was confirmed in 150 million individuals from a large insurance claims dataset. Subsequent studies in >60,000 genotyped BioVU participants confirmed the association of reduced genetically predicted expression of GRIK5 with comorbid vascular and eye diseases. Our studies pioneer an approach that allows a rapid iteration of the discovery of gene-phenotype relationships to the primary genetic mechanism contributing to the pathophysiology of human disease. Our findings also add dimension to the understanding of the biology driven by glutamate receptors such as GRIK5 (also referred to as GLUK5 in protein form) and to mechanisms contributing to human eye diseases.
Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
0 Communities
2 Members
0 Resources
13 MeSH Terms
Insight into the Etiology of Undifferentiated Soft Tissue Sarcomas from a Novel Mouse Model.
Fleming JT, Brignola E, Chen L, Guo Y, Zhao S, Wang Q, Li B, Correa H, Ermilov AN, Dlugosz AA, Chiang C
(2019) Mol Cancer Res 17: 1024-1035
MeSH Terms: Animals, Gene Expression Regulation, Neoplastic, Hedgehog Proteins, Homeodomain Proteins, Humans, Mice, Neoplasm Transplantation, Nerve Tissue Proteins, Sarcoma, Ewing, Signal Transduction, Zebrafish Proteins, Zinc Finger Protein Gli3
Show Abstract · Added April 10, 2019
Aberrant activation of the Hedgehog signaling pathway has been linked to the formation of numerous cancer types, including the myogenic soft tissue sarcoma, embryonal rhabdomyosarcoma (eRMS). Here, we report , a novel mouse model in which human GLI2A, a constitutive activator of Hedgehog signaling, induced undifferentiated sarcomas that were phenotypically divergent from eRMS. Rather, sarcomas arising in mice featured some characteristics that were reminiscent of Ewing sarcoma. Even though it is widely understood that Ewing sarcoma formation is driven by gene fusions, a genetically defined mouse model is not well-established. While gene fusions were not present in sarcomas, precluding their designation as Ewing sarcoma, we did find that GLI2A induced expression of known gene targets essential to Ewing pathogenesis, most notably, . Moreover, we found that naïve mesenchymal progenitors originate tumors in mice. Altogether, our work provides a novel genetic mouse model, which directly connects oncogenic Hedgehog activity to the etiology of undifferentiated soft tissue sarcomas for the first time. IMPLICATIONS: The finding that activation of Gli2 transcription factor is sufficient to induce Ewing-like sarcomas provides a direct transformative role of the Hedgehog signaling pathway in undifferentiated soft tissue sarcoma.
©2019 American Association for Cancer Research.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance.
van der Klaauw AA, Croizier S, Mendes de Oliveira E, Stadler LKJ, Park S, Kong Y, Banton MC, Tandon P, Hendricks AE, Keogh JM, Riley SE, Papadia S, Henning E, Bounds R, Bochukova EG, Mistry V, O'Rahilly S, Simerly RB, INTERVAL, UK10K Consortium, Minchin JEN, Barroso I, Jones EY, Bouret SG, Farooqi IS
(2019) Cell 176: 729-742.e18
MeSH Terms: Adolescent, Adult, Animals, Body Weight, Cell Line, Child, Child, Preschool, Disease Models, Animal, Eating, Energy Metabolism, Female, Genetic Variation, Homeostasis, Humans, Hypothalamus, Leptin, Male, Melanocortins, Mice, Mice, Inbred C57BL, Middle Aged, Nerve Tissue Proteins, Neurons, Obesity, Receptors, Cell Surface, Semaphorins, Young Adult, Zebrafish
Show Abstract · Added April 11, 2019
Hypothalamic melanocortin neurons play a pivotal role in weight regulation. Here, we examined the contribution of Semaphorin 3 (SEMA3) signaling to the development of these circuits. In genetic studies, we found 40 rare variants in SEMA3A-G and their receptors (PLXNA1-4; NRP1-2) in 573 severely obese individuals; variants disrupted secretion and/or signaling through multiple molecular mechanisms. Rare variants in this set of genes were significantly enriched in 982 severely obese cases compared to 4,449 controls. In a zebrafish mutagenesis screen, deletion of 7 genes in this pathway led to increased somatic growth and/or adiposity demonstrating that disruption of Semaphorin 3 signaling perturbs energy homeostasis. In mice, deletion of the Neuropilin-2 receptor in Pro-opiomelanocortin neurons disrupted their projections from the arcuate to the paraventricular nucleus, reduced energy expenditure, and caused weight gain. Cumulatively, these studies demonstrate that SEMA3-mediated signaling drives the development of hypothalamic melanocortin circuits involved in energy homeostasis.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
28 MeSH Terms
Dynamics of Zebrafish Heart Regeneration Using an HPLC-ESI-MS/MS Approach.
Ma D, Tu C, Sheng Q, Yang Y, Kan Z, Guo Y, Shyr Y, Scott IC, Lou X
(2018) J Proteome Res 17: 1300-1308
MeSH Terms: Animals, Chromatography, High Pressure Liquid, Fish Proteins, Gene Ontology, Heart Injuries, Heart Ventricles, Metabolic Networks and Pathways, Molecular Sequence Annotation, Myocardium, Proteomics, Real-Time Polymerase Chain Reaction, Regeneration, Spectrometry, Mass, Electrospray Ionization, Tumor Suppressor Protein p53, Zebrafish
Show Abstract · Added April 3, 2018
Failure to properly repair damaged due to myocardial infarction is a major cause of heart failure. In contrast with adult mammals, zebrafish hearts show remarkable regenerative capabilities after substantial damage. To characterize protein dynamics during heart regeneration, we employed an HPLC-ESI-MS/MS (mass spectrometry) approach. Myocardium tissues were taken from sham-operated fish and ventricle-resected sample at three different time points (2, 7, and 14 days); dynamics of protein expression were analyzed by an ion-current-based quantitative platform. More than 2000 protein groups were quantified in all 16 experiments. Two hundred and nine heart-regeneration-related protein groups were quantified and clustered into six time-course patterns. Functional analysis indicated that multiple molecular function and metabolic pathways were involved in heart regeneration. Interestingly, Ingenuity Pathway Analysis revealed that P53 signaling was inhibited during the heart regeneration, which was further verified by real-time quantitative polymerase chain reaction (Q-PCR). In summary, we applied systematic proteomics analysis on regenerating zebrafish heart, uncovered the dynamics of regenerative genes expression and regulatory pathways, and provided invaluable insight into design regenerative-based strategies in human hearts.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Inherent steroid 17α,20-lyase activity in defunct cytochrome P450 17A enzymes.
Gonzalez E, Johnson KM, Pallan PS, Phan TTN, Zhang W, Lei L, Wawrzak Z, Yoshimoto FK, Egli M, Guengerich FP
(2018) J Biol Chem 293: 541-556
MeSH Terms: Animals, Cytochrome P-450 Enzyme System, Humans, Hydroxysteroids, Protein Conformation, Steroid 17-alpha-Hydroxylase, Zebrafish
Show Abstract · Added March 14, 2018
Cytochrome P450 (P450) 17A1 catalyzes the oxidations of progesterone and pregnenolone and is the major source of androgens. The enzyme catalyzes both 17α-hydroxylation and a subsequent 17α,20-lyase reaction, and several mechanisms have been proposed for the latter step. Zebrafish P450 17A2 catalyzes only the 17α-hydroxylations. We previously reported high similarity of the crystal structures of zebrafish P450 17A1 and 17A2 and human P450 17A1. Five residues near the heme, which differed, were changed. We also crystallized this five-residue zebrafish P450 17A1 mutant, and the active site still resembled the structure in the other proteins, with some important differences. These P450 17A1 and 17A2 mutants had catalytic profiles more similar to each other than did the wildtype proteins. Docking with these structures can explain several minor products, which require multiple enzyme conformations. The 17α-hydroperoxy (OOH) derivatives of the steroids were used as oxygen surrogates. Human P450 17A1 and zebrafish P450s 17A1 and P450 17A2 readily converted these to the lyase products in the absence of other proteins or cofactors (with catalytically competent kinetics) plus hydroxylated 17α-hydroxysteroids. The 17α-OOH results indicate that a "Compound I" (FeO) intermediate is capable of formation and can be used to rationalize the products. We conclude that zebrafish P450 17A2 is capable of lyase activity with the 17α-OOH steroids because it can achieve an appropriate conformation for lyase catalysis in this system that is precluded in the conventional reaction.
0 Communities
1 Members
0 Resources
7 MeSH Terms
Loss of αB-crystallin function in zebrafish reveals critical roles in the development of the lens and stress resistance of the heart.
Mishra S, Wu SY, Fuller AW, Wang Z, Rose KL, Schey KL, Mchaourab HS
(2018) J Biol Chem 293: 740-753
MeSH Terms: Animals, Cardiomyopathies, Edema, Glucocorticoids, Image Processing, Computer-Assisted, Lens, Crystalline, Molecular Chaperones, Mutation, Myocardium, Pericardium, Phenotype, Receptors, Glucocorticoid, Signal Transduction, Stress, Physiological, Transgenes, Zebrafish, alpha-Crystallin A Chain, alpha-Crystallin B Chain
Show Abstract · Added April 3, 2018
Genetic mutations in the human small heat shock protein αB-crystallin have been implicated in autosomal cataracts and skeletal myopathies, including heart muscle diseases (cardiomyopathy). Although these mutations lead to modulation of their chaperone activity , the functions of αB-crystallin in the maintenance of both lens transparency and muscle integrity remain unclear. This lack of information has hindered a mechanistic understanding of these diseases. To better define the functional roles of αB-crystallin, we generated loss-of-function zebrafish mutant lines by utilizing the CRISPR/Cas9 system to specifically disrupt the two αB-crystallin genes, α and α We observed lens abnormalities in the mutant lines of both genes, and the penetrance of the lens phenotype was higher in α than α mutants. This finding is in contrast with the lack of a phenotype previously reported in αB-crystallin knock-out mice and suggests that the elevated chaperone activity of the two zebrafish orthologs is critical for lens development. Besides its key role in the lens, we uncovered another critical role for αB-crystallin in providing stress tolerance to the heart. The αB-crystallin mutants exhibited hypersusceptibility to develop pericardial edema when challenged by crowding stress or exposed to elevated cortisol stress, both of which activate glucocorticoid receptor signaling. Our work illuminates the involvement of αB-crystallin in stress tolerance of the heart presumably through the proteostasis network and reinforces the critical role of the chaperone activity of αB-crystallin in the maintenance of lens transparency.
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
1 Members
0 Resources
18 MeSH Terms
Dynamic Glycosylation Governs the Vertebrate COPII Protein Trafficking Pathway.
Cox NJ, Unlu G, Bisnett BJ, Meister TR, Condon BM, Luo PM, Smith TJ, Hanna M, Chhetri A, Soderblom EJ, Audhya A, Knapik EW, Boyce M
(2018) Biochemistry 57: 91-107
MeSH Terms: Acetylglucosamine, Acylation, Animals, COP-Coated Vesicles, Cell Line, Collagen, Craniofacial Abnormalities, Disease Models, Animal, Glycosylation, Humans, Organelles, Protein Conformation, Protein Processing, Post-Translational, Protein Transport, Vertebrates, Vesicular Transport Proteins, Zebrafish
Show Abstract · Added March 15, 2018
The COPII coat complex, which mediates secretory cargo trafficking from the endoplasmic reticulum, is a key control point for subcellular protein targeting. Because misdirected proteins cannot function, protein sorting by COPII is critical for establishing and maintaining normal cell and tissue homeostasis. Indeed, mutations in COPII genes cause a range of human pathologies, including cranio-lenticulo-sutural dysplasia (CLSD), which is characterized by collagen trafficking defects, craniofacial abnormalities, and skeletal dysmorphology. Detailed knowledge of the COPII pathway is required to understand its role in normal cell physiology and to devise new treatments for disorders in which it is disrupted. However, little is known about how vertebrates dynamically regulate COPII activity in response to developmental, metabolic, or pathological cues. Several COPII proteins are modified by O-linked β-N-acetylglucosamine (O-GlcNAc), a dynamic form of intracellular protein glycosylation, but the biochemical and functional effects of these modifications remain unclear. Here, we use a combination of chemical, biochemical, cellular, and genetic approaches to demonstrate that site-specific O-GlcNAcylation of COPII proteins mediates their protein-protein interactions and modulates cargo secretion. In particular, we show that individual O-GlcNAcylation sites of SEC23A, an essential COPII component, are required for its function in human cells and vertebrate development, because mutation of these sites impairs SEC23A-dependent in vivo collagen trafficking and skeletogenesis in a zebrafish model of CLSD. Our results indicate that O-GlcNAc is a conserved and critical regulatory modification in the vertebrate COPII-dependent trafficking pathway.
0 Communities
1 Members
0 Resources
17 MeSH Terms
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.
0 Communities
1 Members
0 Resources
23 MeSH Terms