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Expression profiling of the RPE in zebrafish smarca4 mutant revealed altered signals that potentially affect RPE and retinal differentiation
(Molecular Vision, 2014-01-06) Zhang, Liyun; Ma, Ping; Collery, Ross; Trowbridge, Sara; Zhang, Mingzhi; Zhong, Wenxuan; Leung, Yuk Fai; Biochemistry and Molecular Biology, School of Medicine
Purpose: The purpose of this study was to develop a framework for analyzing retinal pigment epithelium (RPE) expression profiles from zebrafish eye mutants.
Methods: The fish model we used was SWI/SNF-related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (smarca4), a retinal dystrophic mutant with a previously described retinal phenotype and expression profiles. Histological and Affymetrix GeneChip analyses were conducted to characterize the RPE defects and underlying differential expression, respectively.
Results: Histological analysis revealed that smarca4 RPE was formed, but its differentiation was abnormal. In particular, ultrastructural analysis of smarca4 RPE by transmission electron microscopy demonstrated several defects in melanogenesis. The nature of these defects also suggests that the cytoskeletal dynamics, which are tightly linked with melanogenesis, were impaired in smarca4 RPE. To compare the expression profile of normal wild-type (WT) and smarca4 RPE, the gene expression profiles of microdissected retinas and RPE-attached retinas were measured with Affymetrix GeneChip analysis. The RPE expression values were then estimated from these samples by subtracting the retinal expression values from the expression values of the RPE-attached retinas. A factorial analysis was conducted using the expression values of the RPE, retinal, and whole-embryo samples. Specific rules (contrasts) were built using the coefficients of the resulting fitted models to select for three groups of genes: 1) smarca4-regulated RPE genes, 2) smarca4-regulated retinal genes, and 3) smarca4-regulated RPE genes that are not differentially expressed in the retina. Interestingly, the third group consists of 39 genes that are highly related to cytoskeletal dynamics, melanogenesis, and paracrine and intracellular signal transduction.
Conclusions: Our analytical framework provides an experimental approach to identify differentially-regulated genes in the retina and the RPE of zebrafish mutants in which both of these tissues are affected by the underlying mutation. Specifically, we have used the method to identify a group of 39 genes that can potentially explain the melanogenesis defect in the smarca4 RPE. In addition, several genes in this group are secreted signaling molecules. Thus, this observation further implicates that the smarca4 RPE might play a role in the retinal dystrophic phenotype in smarca4.
TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions
(Springer, 2014) Gallagher, Michael D.; Suh, Eunran; Grossman, Murray; Elman, Lauren; McCluskey, Leo; Van Swieten, John C.; Al-Sarraj, Safa; Neumann, Manuela; Gelpi, Ellen; Ghetti, Bernardino; Rohrer, Jonathan D.; Halliday, Glenda; Van Broeckhoven, Christine; Seilhean, Danielle; Shaw, Pamela J.; Frosch, Matthew P.; International Collaboration for Frontotemporal Lobar Degeneration; Trojanowski, John Q.; Lee, Virginia M. Y.; Van Deerlin, Vivianna; Chen-Plotkin, Alice S.; Pathology and Laboratory Medicine, School of Medicine
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA binding protein of 43kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n=14), with the major allele correlated with later age at death (p=0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n=75), again finding that the major allele associates with later age at death (p=0.016), as well as later age at onset (p=0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
Disturbances in the murine hepatic circadian clock in alcohol-induced hepatic steatosis
(Springer Nature, 2014-01-16) Zhou, Peng; Ross, Ruth A.; Pywell, Cameron M.; Liangpunsakul, Suthat; Duffield, Giles E.; Medicine, School of Medicine
To investigate the role of the circadian clock in the development of alcohol-induced fatty liver disease we examined livers of mice chronically alcohol-fed over 4-weeks that resulted in steatosis. Here we show time-of-day specific changes in expression of clock genes and clock-controlled genes, including those associated with lipid and bile acid regulation. Such changes were not observed following a 1-week alcohol treatment with no hepatic lipid accumulation. Real-time bioluminescence reporting of PERIOD2 protein expression suggests that these changes occur independently of the suprachiasmatic nucleus pacemaker. Further, we find profound time-of-day specific changes to the rhythmic synthesis/accumulation of triglycerides, cholesterol and bile acid, and the NAD/NADH ratio, processes that are under clock control. These results highlight not only that the circadian timekeeping system is disturbed in the alcohol-induced hepatic steatosis state, but also that the effects of alcohol upon the clock itself may actually contribute to the development of hepatic steatosis.
Resumption of Puberty in Girls and Boys Following Removal of the Histrelin Implant
(Elsevier, 2014) Fisher, Marisa M.; Lemay, Deborah; Eugster, Erica A.; Pediatrics, School of Medicine
Objectives: To determine time to menarche in girls and testicular volume increase in boys after removal of a histrelin implant, which causes profound hypothalamic-pituitary-gonadal axis suppression.
Study design: Medical records of patients treated with a histrelin implant were reviewed. Seventy-one patients (56 girls) treated with the histrelin implant were identified, of these patients, 37 explanted girls (68% naïve) and 6 explanted boys (83% naïve) were included in the analysis. Time to menarche after explantation in girls and time to testicular volume increase after explantation in boys were determined. Additional variables investigated included indication for and duration of treatment, history of menarche (girls), previous therapy, and age at beginning and end of histrelin treatment.
Results: Of the girls, 30 were treated for central precocious puberty (CPP), 26 had menarche at an average of 12.75 months after explantation. Of the 30, 7 were treated for other indications, of whom 6 had reached menarche. In girls with CPP, older age at explantation correlated with sooner menarche (P = .04). All boys achieved spontaneous testicular enlargement within 1 year of explantation.
Conclusions: This study documented resumption of puberty after histrelin explantation in treatment naïve and non-naïve boys and girls with and without CPP. Menarche in girls with CPP occurs within a similar timeframe to that observed after other treatment approaches.
Human aortic allograft: an excellent conduit choice for superior vena cava reconstruction
(Springer Nature, 2014-01-15) Spera, Kristyn; Kesler, Kenneth A.; Syed, Amjadullah; Boyd, Jack H.; Surgery, School of Medicine
Superior vena cava (SVC) reconstruction is occasionally required in the treatment of benign and malignant conditions. We report a patient with symptomatic SVC obstruction secondary to mediastinal fibrosis successfully reconstructed with an aortic allograft.