| 1. |
- Archer, Amena, et al.
(författare)
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The Liver X-Receptor (Lxr) Governs Lipid Homeostasis in Zebrafish during Development
- 2012
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Ingår i: Open journal of endocrine and metabolic diseases. - : Scientific Research Publishing. - 2165-7424 .- 2165-7432. ; 2:4, s. 74-81
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Tidskriftsartikel (refereegranskat)abstract
- The liver-X-receptors (LXRs) act as cholesterol sensors and participate in the regulation of lipid and cholesterol metabolism. The objective of this study was to determine the role of LXR during development using the zebrafish model. By in situ hybridization we showed distinct expression of lxr in the brain and the retina in the developing and adult zebrafish. Lxr ligand activation affected the expression of genes involved in lipid metabolism in zebrafish adult brain and eye as well as in zebrafish embryos. Morpholino knock down of lxr resulted in an overall impaired lipid deposition as determined by oil red O staining particularly in the head and around the eyes, and to significantly elevated levels of both total and free cholesterol in the yolk of lxr morphant embryos. The expression of genes involved in lipid and cholesterol metabolism was also changed in the lxr morphants. Furthermore, alcian blue staining revealed malformation of the pharyngeal skeleton in the lxr morphant. Our data show that Lxr is an important component of the regulatory network governing the lipid homeostasis during zebrafish development, which in turn may support a role of Lxr for normal development of the central nervous sytem, including the retina.
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| 2. |
- Cunnea, Paula M, et al.
(författare)
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ERdj5, an endoplasmic reticulum (ER)-resident protein containing DnaJ and thioredoxin domains, is expressed in secretory cells or following ER stress.
- 2003
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 278:2, s. 1059-66
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Tidskriftsartikel (refereegranskat)abstract
- A complex array of chaperones and enzymes reside in the endoplasmic reticulum (ER) to assist the folding and assembly of and the disulfide bond formation in nascent secretory proteins. Here we characterize a novel human putative ER co-chaperone (ERdj5) containing domains resembling DnaJ, protein-disulfide isomerase, and thioredoxin domains. Homologs of ERdj5 have been found in Caenorhabditis elegans and Mus musculus. In vitro experiments demonstrated that ERdj5 interacts via its DnaJ domain with BiP in an ATP-dependent manner. ERdj5 is a ubiquitous protein localized in the ER and is particularly abundant in secretory cells. Its transcription is induced during ER stress, suggesting potential roles for ERdj5 in protein folding and translocation across the ER membrane.
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| 4. |
- O'Farrell, Fergal
(författare)
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A screen for mutations affecting PNS development in Drosophila identifies the trim gene, dappled
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The peripheral nervous system of Drosophila melanogaster contains a variety of sense organs, ranging from the relatively simple four celled bristle organ to the more complex compound eye. The development of each organ type is well described, providing a useful backdrop for functional studies of genes acting in one or more of the many processes involved in organogenesis. We have used the bristle organ to screen for genes affecting PNS development. Two of the candidates recovered via this approach, string (stg, Drosophila cdc25, the universal regulator of the G2 to M phase mitotic transition), and dappled (dpld, a poorly described gene implicated in tumor suppression) were selected for further study. Examination of stg mis-expression phenotypes in the adult bristle organ revealed cell fate transformations corresponding to the generation of two pIIa structural precursor cells at the expense of a neural precursor cell. This transformation most reasonably resulted from an abnormally short G2 arrest, indicating that the time spent in the G2 phase is crucial to correct cell fate determination. dpld is a member of the Tripartite Motif (TRIM) superfamily, members of which are involved in diverse biological processes e.g. proliferation, apoptosis and immune response. dpld belongs to a subgroup of NHL domain containing TRIM proteins, that are known to be involved in tumor suppression. Phylogenetic analysis placed dpld in the lin-41 sub-clade of the TRIM superfamily. A combination of insilico, genetic and cell culture assay approaches showed dpld to be susceptible to miRNA regulation. As homologous genes are also miRNA regulated this regulatory mechanism may be conserved throughout this sub-clade, between vertebrates and invertebrates. Pre-existing loss of function dpld alleles were characterized, however, subsequent complementation studies revealed that characteristic aspects of the described dpld phenotype, in fact mapped outside the dpld locus, and were caused by mutations of nearby genes. The tumor-causing locus was mapped to the Cytb5 gene (mutated in both pre-existing dpld alleles), while the embryonic lethality and PNS phenotype was mapped to the scraps locus. scraps encodes for Drosophila Anillin, known to be required during cytokinesis. We provide the first characterization of scraps null alleles and detail a biased requirement for scraps within neural precursor cells of the embryonic PNS. A novel loss of function dpld allele was recovered. This mutation is lethal, however it does not have an associated tumor phenotype. This finding, together with our complementation study indicates that the existing classification of dpld as a tumor suppressor is inaccurate. Subsequent studies detail dpld requirements in the developing fly retina. There, dpld mutation resulted in excessive proliferation, while conversely, mis-expression caused a reduction. Additionally, and perhaps consequently, cell differentiation was affected. Thus, regulation of proliferation by NHL-TRIM genes seems a conserved feature. We additionally identified a novel Drosophila TRIM gene of the same class as dpld, which we have dubbed another bbox affiliate (abba), bringing the number of NHL containing TRIM genes in Drosophila to four.
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