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Schweigel-Rontgen M.,Leibniz Institute for Farm Animal Biology
Current Topics in Membranes | Year: 2014

The solute carriers families 30 (SLC30; ZnT), 39 (SLC39; ZIP), and 31 (SLC31; CTR) are involved in the essential maintenance of cellular zinc (Zn2+) and copper (Cu2+) homeostasis, respectively.ZnTs mediate Zn2+ extrusion from cells (SLC30A1) or transport Zn2+ into organelles and secretory vesicles/granules (SLC30A2-SLC30A8). SLC39 family members are predominantly localized to the cell membrane where they perform Zn2+ uptake and increase the availability of cytosolic Zn2+. SLC39A1 is ubiquitously expressed, whereas other ZIP transporters (e.g., SLC39A2 and SLC39A3) show a more tissue-restricted expression consistent with organ-specific functions of these proteins.The members A1 (CTR1) and A2 (CTR2) of the SLC31 family of solute carriers belong to a network of proteins that acts to regulate the intracellular Cu2+ concentration within a certain range. SLC31A1 is predominantly localized to the plasma membrane, whereas SLC31A2 is mainly found in intracellular membranes of the late endosome and lysosome. The specific function of SLC31A2 is not known. SLC31A1 is ubiquitously expressed and has been characterized as a high-affinity importer of reduced copper (Cu+). Cu2+ transport function of CTR proteins is associated with oligomerization; SLC31A1 trimerizes and thereby forms a channel-like structure enabling Cu2+ translocation across the cell membrane.The molecular characteristics and structural details (e.g., membrane topology, conserved Zn2+, and Cu2+ binding sites) and mechanisms of translational and posttranslational regulation of expression and/or activity have been described for SLC30 and SLC39 family members, and for SLC31A1.For SLC31A1, data on tissue-specific functions (e.g., in the intestine, heart, and liver) are also available. A link between SLC31A1, immune function, and disorders such as Alzheimer's disease or cancer makes the protein a candidate therapeutic target.In secretory tissues (e.g., the mammary gland and pancreas), Zn2+ transporters of SLC families 30 and 39 are involved in specific functions such as insulin synthesis and secretion, metallation of digestive proenzymes, and transfer of nutrients into milk. Defective or dysregulated Zn2+ metabolism in these organs is associated with disorders such as diabetes and cancer, and impaired Zn2+ secretion into milk. © 2014 Elsevier Inc.

Langbein J.,Leibniz Institute for Farm Animal Biology
Behavioural Processes | Year: 2012

We investigated maze learning in dwarf goats (Capra hircus) and the impact of lateralisation on learning. Lateralisation refers to the collection of phenomena in which external stimuli are perceived and processed differentially on the two sides of the brain and/or certain behaviours are preferentially performed by one side of the body. We trained 29 dwarf goats in a Y-maze, directing them to the opposite alley from that chosen in a free pre-run. In total, 13 goats were trained to the left alley (L-goats) and 16 goats to the right alley (R-goats). Recall of the trained alley was tested three months later. We then analysed reversal learning across 10 reversals. During training, the direction of the alley had an impact on learning. The number of runs required to reach the learning criterion was significantly lower in the L- than the R-goats. The goats recalled the trained alley three months later, with no difference between the L- and the R-goats. During the reversal learning, the reversal only tended to impact learning performance, whereas the directions of the new and the initially trained alley did not. Goats did not adopt a general rule with which to master the maze (e.g., win-stay/lose-shift) across the 10 reversals. Our results indicate a right hemisphere bias in the processing of visuospatial cues in the maze during initial training; however, no such impact was detected during reversal learning. © 2012 Elsevier B.V.

Weitzel J.M.,Leibniz Institute for Farm Animal Biology | Alexander Iwen K.,Universitatsklinikum Schleswig Holstein
Molecular and Cellular Endocrinology | Year: 2011

Thyroid hormone (TH) has profound influence on metabolism that is closely linked to its effect on mitochondrial biogenesis and function. After a single injection of TH into mammals, physiological alterations (e.g. changes in oxygen consumption rates) are detectable after a lag period of ~48. h. This characteristic lag period is somewhat surprising since non-genomic responses are already detectable within minutes, and first genomic responses within some hours after administration of TH. This review provides a model to explain the characteristic lag period: TH regulates a first series of TH target genes via classical activation of gene expression by binding to thyroid hormone response elements. Some directly regulated target genes serve as intermediate factors and subsequently regulate a second series of indirect TH target genes. Intermediate factors are transcription factors (such as NRF-1, NRF-2 and PPARγ) and transcriptional coactivators (such as PGC-1α and PGC-1β). In concert with several post-translational modifications, these intermediate factors orchestrate the physiological response to thyroid hormone in vivo. © 2011 Elsevier Ireland Ltd.

Schmelzer C.,Leibniz Institute for Farm Animal Biology | Doring F.,University of Kiel
Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis | Year: 2012

Coenzyme Q10 (CoQ10) is an essential component for electron transport in the mitochondrial respiratory chain and serves as cofactor in several biological processes. The reduced form of CoQ10 (ubiquinol, Q10H2) is an effective antioxidant in biological membranes. During the last years, particular interest has been grown on molecular effects of CoQ10 supplementation on mechanisms related to DNA damage prevention. This review describes recent advances in our understanding about the impact of CoQ10 on genomic stability in cells, animals and humans. With regard to several in vitro and in vivo studies, CoQ10 provides protective effects on several markers of oxidative DNA damage and genomic stability. In comparison to the number of studies reporting preventive effects of CoQ10 on oxidative stress biomarkers, CoQ10 intervention studies in humans with a direct focus on markers of DNA damage are limited. Thus, more well-designed studies in healthy and disease populations with long-term follow up results are needed to substantiate the reported beneficial effects of CoQ10 on prevention of DNA damage. © 2011 Elsevier B.V.

Spitschak M.,Leibniz Institute for Farm Animal Biology | Vanselow J.,Leibniz Institute for Farm Animal Biology
General and Comparative Endocrinology | Year: 2012

Transformation of the estrogen producing large dominant follicle into a functional progesterone producing corpus luteum involves profound and well-orchestrated changes in cell type-specific gene expression profiles, possibly involving epigenetic mechanisms of gene silencing. As an experimental paradigm to examine the involvement of de novo DNA methylation in the process of luteinization, the transcript abundance and promoter-specific DNA methylation levels of CYP19A1, which encodes the key enzyme for estrogen biosynthesis, were analyzed in enzymatically dispersed and purified large granulosa luteal cells of early- to mid-cycle bovine corpora lutea. To characterize the morphology and physiology of isolated corpora lutea, their weights and the respective plasma progesterone levels were analyzed. Transcript abundance of CYP19A1, HSD3B1, GHR, and of LHGCR was quantified by real-time PCR. Methylation levels were analyzed by bisulfite direct sequencing. The data indicated that corpora lutea weights and plasma progesterone levels significantly increased during the early luteal phase (days 3-6 of the cycle). The growth of small and large luteal cells was particularly pronounced between days 3 and 4. Large luteal cells are characterized by high HSD3B1 and GHR, but low LHCGR transcript abundance, whereas CYP19A1 expression was very low or undetectable. The DNA methylation levels of the main ovarian CYP19A1 promoter P2 significantly increased from day 5. In conclusion, the data indicated de novo DNA methylation approximately five days after the luteinizing hormone-induced down-regulation of CYP19A1 expression, suggesting that DNA methylation during the early luteal phase might play a role for permanent silencing of previously down-regulated genes. © 2012 Elsevier Inc.

Gimsa U.,Leibniz Institute for Farm Animal Biology | Mitchison N.A.,University College London | Brunner-Weinzierl M.C.,Otto Von Guericke University of Magdeburg
Mediators of Inflammation | Year: 2013

Astrocytes have many functions in the central nervous system (CNS). They support differentiation and homeostasis of neurons and influence synaptic activity. They are responsible for formation of the blood-brain barrier (BBB) and make up the glia limitans. Here, we review their contribution to neuroimmune interactions and in particular to those induced by the invasion of activated T cells. We discuss the mechanisms by which astrocytes regulate pro- and anti-inflammatory aspects of T-cell responses within the CNS. Depending on the microenvironment, they may become potent antigen-presenting cells for T cells and they may contribute to inflammatory processes. They are also able to abrogate or reprogram T-cell responses by inducing apoptosis or secreting inhibitory mediators. We consider apparently contradictory functions of astrocytes in health and disease, particularly in their interaction with lymphocytes, which may either aggravate or suppress neuroinflammation. © 2013 Ulrike Gimsa et al.

Baufeld A.,Leibniz Institute for Farm Animal Biology | Vanselow J.,Leibniz Institute for Farm Animal Biology
Cell and Tissue Research | Year: 2013

Cultured ovarian granulosa cells are essential models to study molecular mechanisms of gene regulation during folliculogenesis. Here, we characterize primary tissue culture models for bovine granulosa cells by morphological and physiological parameters and by novel molecular luteinization markers, as transcript abundance and DNA methylation levels. The data show that: (1) collagen substrate increased the number of attached, viable cells; (2) the expression of the key transcripts of estrogen synthesis, CYP19A1, could be induced and maintained in granulosa cells from small to medium but not from large follicles, whereas (3) only granulosa cells from large but not from smaller follicles were responsive to LH; (4) serum supplementation unfavorably transformed the cellular phenotype, induced proliferation and PCNA expression, reduced or abolished the transcript abundance of steroidogenic key genes and of gonadotropin receptor genes, CYP11A1, CYP19A1, FSHR and LHCGR but, however, did not increase the abundance of the luteinization-specific marker transcripts PTGS2, PTX3, RGS2 and VNN2; but (5) by increasing the plating density, estradiol production and the abundance of CYP19A1 transcripts, in particular those derived from the main ovarian promoter P2, were decreased concurrently leaving P2-specific DNA methylation levels unchanged, whereas progesterone secretion was stimulated and the expression of both luteinization-specific marker transcripts, RGS2 and VNN2, was significantly induced. From these data, we conclude that increasing the plating density induces a different, partly complementary, physiological and gene expression profile in cultured bovine granulosa cells and drives the cells towards an early post-LH stage of luteinization, even in the absence of luteinizing agents. © 2013 Springer-Verlag Berlin Heidelberg.

Weikard R.,Leibniz Institute for Farm Animal Biology | Hadlich F.,Leibniz Institute for Farm Animal Biology | Kuehn C.,Leibniz Institute for Farm Animal Biology
BMC Genomics | Year: 2013

Background: Deep RNA sequencing (RNAseq) has opened a new horizon for understanding global gene expression. The functional annotation of non-model mammalian genomes including bovines is still poor compared to that of human and mouse. This particularly applies to tissues without direct significance for milk and meat production, like skin, in spite of its multifunctional relevance for the individual. Thus, applying an RNAseq approach, we performed a whole transcriptome analysis of pigmented and nonpigmented bovine skin to describe the comprehensive transcript catalogue of this tissue. Results: A total of 39,577 unique primary skin transcripts were mapped to the bovine reference genome assembly. The majority of the transcripts were mapped to known transcriptional units (65%). In addition to the reannotation of known genes, a substantial number (10,884) of unknown transcripts (UTs) were discovered, which had not previously been annotated. The classification of UTs was based on the prediction of their coding potential and comparative sequence analysis, subsequently followed by meticulous manual curation. The classification analysis and experimental validation of selected UTs confirmed that RNAseq data can be used to amend the annotation of known genes by providing evidence for additional exons, untranslated regions or splice variants, by approving genes predicted in silico and by identifying novel bovine loci. A large group of UTs (4,848) was predicted to potentially represent long noncoding RNA (lncRNA). Predominantly, potential lncRNAs mapped in intergenic chromosome regions (4,365) and therefore, were classified as potential intergenic lncRNA. Our analysis revealed that only about 6% of all UTs displayed interspecies conservation and discovered a variety of unknown transcripts without interspecies homology but specific expression in bovine skin.Conclusions: The results of our study demonstrate a complex transcript pattern for bovine skin and suggest a possible functional relevance of novel transcripts, including lncRNA, in the modulation of pigmentation processes. The results also indicate that the comprehensive identification and annotation of unknown transcripts from whole transcriptome analysis using RNAseq data remains a tremendous future challenge. © 2013 Weikard et al.; licensee BioMed Central Ltd.

Anand-Ivell R.,Leibniz Institute for Farm Animal Biology | Ivell R.,Leibniz Institute for Farm Animal Biology
Molecular and Cellular Endocrinology | Year: 2014

The relaxin family of peptide hormones are structurally closely related to one another sharing a heterodimeric A-B structure, like that of insulin. They may also be active as unprocessed B-C-A pro-forms. Relaxin has been shown to pay a key role within the ovary, being involved in follicle growth, and ovulation. Relaxin is produced in large amounts also by the corpus luteum where it acts as an endocrine hormone positively affecting implantation, placentation and vascularization during the all-important first trimester phase of pregnancy establishment. Relaxin exerts its functions via the receptor RXFP1. Insulin-like peptide 3 (INSL3) in contrast acts through the related receptor RXFP2, and plays an essential role in the production of androgens within growing antral follicles. INSL3 is also produced in large amounts by the male fetus shortly after sex determination, where it controls the first transabdominal phase of testicular descent. However, this fetal INSL3 is also able to influence placental and maternal physiology, indicating associations with later preeclampsia and/or fetal growth restriction. Other members of this relaxin-like family of peptides, such as INSL4, INSL5 and INSL6 are less well studied, though all suggest modulatory roles in ovarian and/or placental function. © 2013 Elsevier Ireland Ltd.

Brenmoehl J.,Leibniz Institute for Farm Animal Biology | Hoeflich A.,Leibniz Institute for Farm Animal Biology
Mitochondrion | Year: 2013

In this review, we discuss the dual control of mitochondrial biogenesis and energy metabolism by silent information regulator-1 and -3 (SIRT1 and SIRT3). SIRT1 activates the peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α)-mediated transcription of nuclear and mitochondrial genes encoding for proteins promoting mitochondria proliferation, oxidative phosphorylation and energy production, whereas SIRT3 directly acts as an activator of proteins important for oxidative phosphorylation, tricarboxylic acid (TCA) cycle and fatty-acid oxidation and indirectly of PGC-1α and AMP-activated protein kinase (AMPK). The complex network involves different cellular compartments, transcriptional activation, post-translational modification and a plethora of secondary effectors. Overall, the mode of interaction between both sirtuin family members may be considered as a prominent case of molecular job-sharing. © 2013 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

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