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1.
Invest Ophthalmol Vis Sci ; 51(7): 3792-9, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20207966

ABSTRACT

PURPOSE. Jeune's asphyxiating thoracic dystrophy (JATD) is an autosomal recessive disorder with symptoms of retinal degeneration, kidney cysts, and chondrodysplasia and results from mutations in the ift80 gene. This study was conducted to characterize zebrafish lacking ift80 function for photoreceptor degeneration and defects in ciliogenesis to establish zebrafish as a vertebrate model for visual dysfunction in JATD and to determine whether ift80 interacts genetically with Bardet-Biedl syndrome (BBS) genes. METHODS. Zebrafish were injected with morpholinos (MOs) targeted to the ift80 gene. Retinas were analyzed by histology, transmission electron microscopy, and immunohistochemistry. Ear and kidney cilia were analyzed by whole-mount immunostaining. Intraflagellar transport (IFT) particle composition was subjected to Western blot analysis. Genetic interactions were tested by coinjection of MOs against ift80 and bbs4 or bbs8 followed by in situ hybridization. RESULTS. Zebrafish lacking ift80 function exhibited defects in photoreceptor outer segment formation and photoreceptor death. Staining with opsin antibodies revealed opsin mislocalization in both rods and cones. Ultrastructural analysis showed abnormal disc stacking and shortened photoreceptor outer segments. The kinocilia of the ear and motile cilia in the kidney were shorter and reduced in number. Western blot analysis revealed a slight increase in the stability of other IFT proteins. Coinjection of MOs against ift80 and BBS genes led to convergent-extension defects. CONCLUSIONS. Zebrafish lacking ift80 exhibited defects characteristic of JATD. Because the developing outer segments degenerated, Ift80 could possibly act as a maintenance factor for the IFT particle.


Subject(s)
Asphyxia/pathology , Carrier Proteins/physiology , Disease Models, Animal , Exostoses, Multiple Hereditary/pathology , Photoreceptor Cells, Vertebrate/pathology , Retinal Degeneration/pathology , Thoracic Diseases/pathology , Zebrafish Proteins/physiology , Animals , Asphyxia/genetics , Blotting, Western , Cell Survival/physiology , Electrophoresis, Polyacrylamide Gel , Exostoses, Multiple Hereditary/genetics , Fluorescent Antibody Technique, Indirect , Gene Silencing/drug effects , In Situ Hybridization , In Situ Nick-End Labeling , Kidney Diseases, Cystic/genetics , Kidney Diseases, Cystic/pathology , Retinal Degeneration/genetics , Reverse Transcriptase Polymerase Chain Reaction , Thoracic Diseases/genetics , Zebrafish
2.
Dev Dyn ; 238(7): 1744-59, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19517571

ABSTRACT

Cilia formation requires intraflagellar transport (IFT) proteins. Recent studies indicate that mammalian Hedgehog (Hh) signaling requires cilia. It is unclear, however, if the requirement for cilia and IFT proteins in Hh signaling represents a general rule for all vertebrates. Here we examine zebrafish ift57, ift88, and ift172 mutants and morphants for defects in Hh signaling. Although ift57 and ift88 mutants and morphants contained residual maternal protein, the cilia were disrupted. In contrast to previous genetic studies in mouse, mutations in zebrafish IFT genes did not affect the expression of Hh target genes in the neural tube and forebrain and had no quantitative effect on Hh target gene expression. Zebrafish IFT mutants also exhibited no dramatic changes in the craniofacial skeleton, somite formation, or motor neuron patterning. Thus, our data indicate the requirement for cilia in the Hh signal transduction pathway may not represent a universal mechanism in vertebrates.


Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Cilia/genetics , Hedgehog Proteins/physiology , Zebrafish Proteins/physiology , Zebrafish/genetics , Adaptor Proteins, Signal Transducing/genetics , Animals , Animals, Genetically Modified , Carrier Proteins/genetics , Carrier Proteins/physiology , Embryo, Nonmammalian , Gene Expression Regulation, Developmental/drug effects , Gene Knockdown Techniques , Hedgehog Proteins/genetics , Hedgehog Proteins/metabolism , Mutant Proteins/physiology , Mutation/physiology , Signal Transduction/drug effects , Signal Transduction/genetics , Signal Transduction/physiology , Veratrum Alkaloids/pharmacology , Zebrafish/embryology , Zebrafish Proteins/genetics
3.
Trauma Violence Abuse ; 8(3): 314-30, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17596348

ABSTRACT

A growing body of evidence suggests that social conflict is associated with inflammatory disease onset and exacerbations in multiple sclerosis (MS) patients and in animal models of MS. This review illustrates how animal research can be used to elucidate the biobehavioral mechanisms underlying the adverse health effects of social conflict. The authors review studies indicating that social conflict exacerbates a virally initiated animal model of MS. This research suggests that the deleterious effects of social conflict may be partially mediated by stress-induced increases in pro-inflammatory cytokine levels in the central nervous system. In addition, they provide evidence that the adverse health effects of social conflict can be prevented by blocking the stress-induced increases in cytokine activity. This suggests that interventions designed to prevent or reverse the stress-induced increases in cytokine activity may be able to prevent or reverse some of the negative health effects of social conflict in humans.


Subject(s)
Disease Models, Animal , Multiple Sclerosis/physiopathology , Social Conditions , Stress, Psychological/physiopathology , Animals , Anxiety , Cytokines/metabolism , Multiple Sclerosis/immunology , Physical Conditioning, Animal , Social Isolation , T-Lymphocytes/metabolism
4.
Brain Behav Immun ; 21(8): 1083-95, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17591434

ABSTRACT

Prior exposure to social disruption stress (SDR) exacerbates both the acute and chronic phase of Theiler's murine encephalomyelitis virus infection (TMEV; [Johnson, R.R., Storts, R., Welsh, T.H., Jr., Welsh, C.J., Meagher, M.W., 2004. Social stress alters the severity of acute Theiler's virus infection. J. Neuroimmunol. 148, 74--85; Johnson, R.R., Prentice, T.W., Bridegam, P., Young, C.R., Steelman, A.J., Welsh, T.H., Welsh, C.J.R., Meagher, M.W., 2006. Social stress alters the severity and onset of the chronic phase of Theiler's virus infection. J. Neuroimmunol. 175, 39--51]). However, the neuroimmune mechanism(s) mediating this effect have not been determined. The present study examined whether stress-induced increases in the proinflammatory cytokine interleukin-6 (IL-6) contributes to the adverse effects of SDR on acute TMEV infection. Experiment 1 demonstrated that SDR increases central and peripheral levels of IL-6 and that this effect is reversed by intracerebral ventricular infusion of neutralizing antibody to IL-6 prior to each of six SDR sessions. Although SDR reduced the sensitivity of spleen cells to the anti-inflammatory effects of corticosterone, the neutralizing antibody to IL-6 did not alter this effect. To investigate whether stress-induced increases in IL-6 contribute to the exacerbation of acute TMEV infection, Experiment 2 examined whether intracerebral administration of neutralizing antibody to IL-6 during SDR would prevent the subsequent exacerbation of acute TMEV infection. Experiment 3 then replaced the social stress with intracerebral infusion of IL-6 to assess sufficiency. As expected, prior exposure to SDR subsequently increased infection-related sickness behaviors, motor impairment, CNS viral titers, and CNS inflammation. These deleterious effects of SDR were either prevented or significantly attenuated by intracerebral infusion of neutralizing antibody to IL-6 during the stress exposure period. However, infusion of IL-6 alone did not mimic the adverse effects of SDR. We conclude that IL-6 is necessary but not sufficient to exacerbate acute TMEV infection.


Subject(s)
Cardiovirus Infections/immunology , Interleukin-6/immunology , Stress, Psychological/immunology , Theilovirus/immunology , Analysis of Variance , Animals , Brain/immunology , Brain/virology , Cardiovirus Infections/complications , Disease Models, Animal , Exploratory Behavior/physiology , Glucocorticoids/blood , Interleukin-6/blood , Male , Mice , Mice, Inbred BALB C , Motor Activity/immunology , Multiple Sclerosis/immunology , Multiple Sclerosis/psychology , Neuroimmunomodulation , Sick Role , Social Environment , Spinal Cord/immunology , Spinal Cord/virology , Spleen/cytology , Spleen/metabolism , Stress, Psychological/complications , Stress, Psychological/virology
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