Retinal photoreceptors are apoptosis-competent in the absence of JunD/AP-1.
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Adaptor Protein Complex alpha Subunits↗
Biomedical subjects
C Grimm
Publications and source records attributed to C Grimm.
Isolation and embryonic expression of the novel mouse gene Hic1, the homologue of HIC1, a candidate gene for the Miller-Dieker syndrome.
The human gene HIC1 (hypermethylated in cancer) maps to chromosome 17p13.3 and is deleted in the contiguous gene disorder Miller-Dieker syndrome (MDS) [Makos-Wales et al. (1995) Nature Med., 1, 570-577; Chong et al. (1996) Genome Res., 6, 735-741]. We isolated the murine homologue Hic1, encoding a zinc-finger protein with a poxvirus and zinc-finger (POZ) domain and mapped it to mouse chromosome 11 in a region exhibiting conserved synteny to human chromosome 17. Comparison of genomic and cDNA sequences predicts two exons for the murine Hic1. The second exon exhibits 88% identity to the human HIC1 on DNA level. During embryonic development, Hic1 is expressed in mesenchymes of the sclerotomes, lateral body wall, limb and cranio-facial regions embedding the outgrowing peripheral nerves during their differentiation. During fetal development, Hic1 additionally is expressed in mesenchymes apposed to precartilaginous condensations, at many interfaces to budding epithelia of inner organs, and weakly in muscles. We observed activation of Hic1 expression in the embryonic anlagen of many tissues displaying anomalies in MDS patients. Besides lissencephaly, MDS patients exhibit facial dysmorphism and frequently additional birth defects, e.g. anomalies of the heart, kidney, gastrointestinal tract and the limbs (OMIM 247200). Thus, HIC1 activity may correlate with the defective development of the nose, jaws, extremities, gastrointestinal tract and kidney in MDS patients.
Abnormalities, Multiple↗
Activation of the protein tyrosine phosphatase SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine kinase Jak1 and limits acute-phase protein expression.
Stimulation of the interleukin-6 (IL-6) signalling pathway occurs via the IL-6 receptor-glycoprotein 130 (IL-6R-gp130) receptor complex and results in the regulation of acute-phase protein genes in liver cells. Ligand binding to the receptor complex leads to tyrosine phosphorylation and activation of Janus kinases (Jak), phosphorylation of the signal transducing subunit gp130, followed by recruitment and phosphorylation of the signal transducer and activator of transcription factors STAT3 and STAT1 and the src homology domain (SH2)-containing protein tyrosine phosphatase (SHP2). The tyrosine phosphorylated STAT factors dissociate from the receptor, dimerize and translocate to the nucleus where they bind to enhancer sequences of IL-6 target genes. Phosphorylated SHP2 is able to bind growth factor receptor bound protein (grb2) and thus might link the Jak/STAT pathway to the ras/raf/mitogen-activated protein kinase pathway. Here we present data on the dose-dependence, kinetics and kinase requirements for SHP2 phosphorylation after the activation of the signal transducer, gp130, of the IL-6-type family receptor complex. When human fibrosarcoma cell lines deficient in Jak1, Jak2 or tyrosine kinase 2 (Tyk2) were stimulated with IL-6-soluble IL-6R complexes it was found that only in Jak1-, but not in Jak 2- or Tyk2-deficient cells, SHP2 activation was greatly impaired. It is concluded that Jak1 is required for the tyrosine phosphorylation of SHP2. This phosphorylation depends on Tyr-759 in the cytoplasmatic domain of gp130, since a Tyr-759-->Phe exchange abrogates SHP2 activation and in turn leads to elevated and prolonged STAT3 and STAT1 activation as well as enhanced acute-phase protein gene induction. Therefore, SHP2 plays an important role in acute-phase gene regulation.
Antigens, CD↗
Aphakia (ak), a mouse mutation affecting early eye development: fine mapping, consideration of candidate genes and altered Pax6 and Six3 gene expression pattern.
The homozygous mouse mutant aphakia (ak) has been characterized by bilaterally aphakic eyes without a pupil [Varnum DS, Stevens, LC (1968): J Hered 59:147-150]. The mutation was mapped to chromosome 19 [Varnum DS, Stevens, LC (1975): Mouse News Lett 53:35]. Our linkage studies yielded a precise localization of the ak gene 0.6 +/- 0.3 cM proximal to the microsatellite marker D19Mit10 and 0.7 +/- 0.4 cM distal to D19Mit4 and D19Mit91. No recombination was found with the marker D19Mit9 among 418 backcross offspring tested. The developmental control gene Pax2 mapped 11.0 +/- 3.5 cM proximal to ak and is excluded as a candidate gene. Sequence analysis of Fgf8 and Chuk1, which are localized close to the marker D19Mit10, detected no mutations in the ak/ak mutants. Histological analysis of homozygous mutants suggested the arrest of lens development at the lens stalk stage, a transient morphological structure during the formation of the lens vesicle. In the lens remnants, Pax6 and Six3 are expressed, whereas in the persisting lens stalk only Pax6 was detected. The expression pattern of Pax2 appeared normal; Cryaa expression could not be detected. As a consequence of the arrested lens development, other ocular tissues that require for their development information from the intact lens, such as iris, ciliary muscle, retina, and vitreous body, are absent or formed abnormally.
Animals↗
A comparison between electric source localisation and fMRI during somatosensory stimulation.
The present study investigates the electric source localisation of somatosensory evoked potentials (SEPs) using high-resolution EEG (61 scalp electrodes) considering the individual brain morphology as obtained from magnetic resonance images (MRI). A comparison with the activation maps in fMRI under the same somatosensory stimulation paradigm was done. The somatosensory evoked potentials (SEPs) to electrical stimulation of the right median nerve were collected from the scalp of 8 healthy right-handed subjects. The source reconstruction for the 20 ms SEP component was performed by using a single moving dipole model as a source model and a spherical three-shell model as a head model. In 6 of the subjects fMRI was performed using the same electric stimulation of the right median nerve. The source location of the 20 ms SEP component was found to be within the postcentral gyrus. The fMRI activation maps were also located in the postcentral gyrus when using the same somatosensory stimulation paradigm. The appropriateness of using high-resolution EEG and fMRI in the functional localisation of the primary somatosensory cortex is discussed.
Adult↗
Estimation of the accuracy of a surface matching technique for registration of EEG and MRI data.
OBJECTIVES: We developed a method to register EEG and MRI data used for the source reconstruction of electric brain activity. METHODS: The method is based on matching of the head surfaces as obtained by 3D scanning after the EEG recording, and by segmentation of MRI data. The registration accuracy was estimated by calculating the residual error of the surface matching and its intra-individual and inter-individual variability. In addition, the test-retest reliability concerning the transformation of electrode positions was studied, to estimate how inaccuracies resulting from the 3D scanning of the head surface translate into registration uncertainty. RESULTS: For 61 measurements, performed on 20 subjects, the average root mean square of the Euclidean distances between the 3D-scanned and the MRI-derived head surfaces amounted to 3.4 mm. An inter-individual standard deviation of 0.24 mm, and an intraindividual standard deviation of 0.003-0.31 mm proved a high inter- and intra-subject stability of the surface matching technique. The variation of transformation results when studying the test-retest reliability amounted to 1.6 mm on average. The maximum error of transformation was smaller than the diameter of the electrodes. CONCLUSIONS: The findings suggest that the surface matching technique is a precise method for determination of the transformation of electrode positions and MRI data into a single co-ordinate system and can successfully be used in a routine laboratory setting.
Brain↗
Apoptotic cell death in retinal degenerations.
Apoptosis is a regulated mode of single cell death that involves gene expression in many instances and occurs under physiological and pathological conditions in a large variety of systems. We briefly summarize major features of apoptosis in general and describe the occurrence of apoptosis in the retina in different situations that comprise animal models of retinitis pigmentosa, light-induced lesions, histogenesis during development, and others. Apoptosis can be separated into several phases: the induction by a multitude of stimuli, the effector phase in which the apoptotic signal is transmitted to the cellular death machinery, the excecution period when proteolytic cascades are activated, and the phagocytic removal of cellular remnants. Control mechanisms for retinal apoptosis are only beginning to be clarified. Potential apoptotic signal transducers were investigated in our laboratory, including metabolites of arachidonic acid and downstream mediators of signaling molecules such as transcription factors. Work in our laboratory revealed an essential role of the immediate-early gene product c-Fos in light-induced apoptosis. c-Fos is a member of the AP-1 family of transcription factors and, together with other members of this family, it may regulate apoptosis in the central nervous system. Expression of the c-fos gene in the retina can be evoked by light exposure and follows a diurnal rhythm. Future studies will have to clarify how light can control the expression of specific genes, and specifically, the role of c-fos and other genes of retinal apoptosis including potential target genes and signaling pathways.
Animals↗
The ECS1 gene of Arabidopsis encodes a plant cell wall-associated protein and is potentially linked to a locus influencing resistance to Xanthomonas campestris.
The interaction between Arabidopsis and Xanthomonas campestris pv. campestris (Xcc) provides a useful model system to identify components that are involved in incompatible interactions of this phytopathogen and cruciferous plants. We have previously described a new gene from Arabidopsis thaliana, ECS1 (formerly CXC750), which showed an ecotype-specific expression pattern, although homologous sequences are present in the genomes of all ecotypes tested. Interestingly, ECS1 mRNA transcripts were only detected in ecotypes which showed the resistant phenotype against Xcc race 750. Subsequent genetic studies with F3 progeny of a cross between a Xcc750 resistant ecotype (Col-0) and a Xcc750 sensitive ecotype (Oy-0) revealed segregation of the ECS1RNA-phenotype away from the Xcc750 susceptible phenotype in one out of 16 F3 families. In addition, transformation of Xcc750 sensitive plants that did not express ECS1, with a constitutively transcribed ECS1 gene, did not lead to the resistant phenotype in the transgenic plants. From these results we conclude that ECS1 is not a Xcc750 resistance gene, but the genetic data indicate that ECS1 is linked to a locus influencing resistance to Xcc750. ECS1 was localized to YACs 3H12 and 12F3 of the CIC library, which map to chromosome 1. Subcellular localization of the gene product indicated that the ECS1 protein is associated with the plant cell wall. Further molecular investigation of 10 ecotypes revealed the utility of ECS1 as a new marker for chromosome 1, which is detectable by RFLP, PCR or expression analysis.
Arabidopsis↗
A PCR-ELISA for the detection of potential fumonisin producing Fusarium species.
A PCR-ELISA for the detection of potential fumonisin producing Fusarium species has been developed, using the ribosomal ITS1 sequence as target. For this purpose, the sequences of the ITS1 regions of different fumonisin producing Fusarium species have been determined and compared to the sequences of fumonisin non-producing species. In general, the ITS1 sequences were highly homologous. However, some minor sequence polymorphisms were detected, which differentiates potential fumonisin producing Fusarium species from non-producing species. By using these sequence differences, a PCR-ELISA for potential fumonisin producing Fusarium species was developed. All other ubiquitously occurring food-borne fungi tested showed negative results with this test.
Base Sequence↗
Fungicidal properties, sterol binding, and proteolytic resistance of the synthetic peptide D4E1.
The fungicidal properties of the synthetic peptide D4E1 were studied with nongerminated and germinating conidia of Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Fusarium moniliforme, and Fusarium oxysporum. The minimal lethal concentrations (MLC) needed to kill 100% of germinating conidia of A. fumigatus, A. flavus, and A. niger were 12.5, 12.5, and 25 microM, respectively. The MLC value for nongerminated and germinating conidia of both Fusarium spp. was 3.0 microM. Except for A. fumigatus, D4E1 was inactive against the nongerminated conidia of the Aspergillus spp. Physicochemical studies showed D4E1 complexed with ergosterol, a sterol present in conidial walls. Cholesterol, present in nongerminated conidia of F. moniliforme, had a greater affinity for D4E1 than did ergosterol. D4E1 was more resistant to fungal and plant protease degradation than the natural peptide, cecropin A. These in vitro results suggest D4E1 is a candidate for transgenic expression in plants to enhance host resistance to fungal infection.
Antifungal Agents↗
Fungicidal and binding properties of the natural peptides cecropin B and dermaseptin.
In vitro fungicidal properties of cecropin B and dermaseptin were explored using non-germinating and germinating conidia from Aspergillus flavus, A. fumigatus, A. niger, Fusarium n2oniliforme and F oxysporum. Cecropin B produced LD50 values for germinating A. flavus, A. fumigatus and A. niger conidia of 30, 0.5 and 2.0 microM, respectively, while dermaseptin gave LD50 values of 4.0, 0.05 and 2.0 microM, respectively. Cecropin B produced an LD50 value of 0.2 microM for non-germinating F. moniliforme and F. oxysporum conidia, while dermaseptin did not reduce either as much as 50% at any level tested. LD50 levels for CB were 0.2 and 0.1 microM, respectively, for germinating F. moniliforme and F. oxysporum conidia. Dermaseptin was less effective, giving LD50 values for germinating F. moniliforme and F. oxysporum conidia of 0.3 and 0.8 microM, respectively. Neither peptide reduced conidial viabilities of non-germinating Aspergillus spp. Physicochemical studies indicated cecropin B and dermaseptin bound to ergosterol and cholesterol, conidial wall constituents, but not to chitin or beta-1,3-glucan.
Amino Acid Sequence↗
Light-induced cell death of retinal photoreceptors in the absence of p53.
PURPOSE: Cell death by apoptosis is essential for normal development and tissue homeostasis, and it is involved also in a variety of pathologic processes. Apoptosis is the final common pathway of photoreceptor cell death in retinal dystrophies and degeneration. So far, little is known about genes regulating apoptosis in the retina. The tumor-suppressor gene product p53 is a potent regulator of apoptosis in numerous systems. However, p53-independent apoptotic pathways also have been described. In this study the authors investigated the role of p53 in the light-induced apoptosis of retinal photoreceptors using mice lacking p53. METHODS: Free-moving p53-/- and p53+/+ mice were dark adapted and were exposed to 8,500 or 15,000 lux of diffuse, cool, white fluorescent light for 2 hours. Animals were killed before and immediately after light exposure or at 12 hours in darkness after light exposure. Eyes were enucleated and processed for light and electron microscopy and histochemistry (TdT-dUTP terminal nick-end labeling method). Isolated retinas were subjected to the extraction of total retinal DNA. Electroretinogram (ERG) recordings were performed at all time points. RESULTS: Morphologic, biochemical, histochemical, and ERG analysis showed that the retinas of untreated p53-/- mice and wild-type control mice were structurally and functionally indistinguishable. After exposure to diffuse white fluorescent light, light-induced photoreceptor cell death was analyzed and was found to be the same in both groups of mice. CONCLUSIONS: These data suggest that light-induced apoptosis of photoreceptors is independent of functional p53.
Animals↗
Retinal degeneration in the rd mouse in the absence of c-fos.
PURPOSE: Apoptosis is the final common death pathway of photoreceptors in light-induced retinal degeneration and in several animal models for retinal dystrophy. To date, little is known about gene regulation of apoptosis in the retina. The expression of the immediate early gene c-fos is upregulated concomitant with apoptosis in light-induced photoreceptor degeneration and in the rd mouse, an animal model for inherited retinal degeneration. In a recent study it was shown that c-Fos is essential for light-induced apoptosis of photoreceptors in vivo. To determine whether c-Fos is also involved in the apoptotic pathway of inherited retinal degeneration, rd/rd, c-fos -/- double-mutant mice have been generated. METHODS: Double-mutant mice (rd/rd, c-fos -/-) were crossbred from c-fos+/- mice and rd/rd mice. Their genotype was determined by polymerase chain reaction analysis of genomic DNA. Wild-type control mice and homozygous rd mice were killed at 2-day intervals from postnatal day (P)9 through P21. Double-mutant mice were killed at postnatal days P9, P11, P13, P15, and P21. To determine levels of apoptosis in the retina, eyes were enucleated and processed for light microscopy and in situ nick-end labeling. Total retinal DNA was extracted from isolated retinas for DNA fragmentation analysis. RESULTS: Morphologic, histochemical, and biochemical analyses showed that the time course of apoptosis and the outcome of photoreceptor degeneration in rd/rd, c-fos-/- double-mutant mice was indistinguishable from that in rd mice carrying functional c-fos. CONCLUSIONS: These data suggest that in contrast to its role in light-induced photoreceptor degeneration, c-Fos is not essential for apoptosis in the rd mouse.
Animals↗
The constitutive transport element (CTE) of Mason-Pfizer monkey virus (MPMV) accesses a cellular mRNA export pathway.
The constitutive transport elements (CTEs) of type D retroviruses are cis-acting elements that promote nuclear export of incompletely spliced mRNAs. Unlike the Rev response element (RRE) of human immunodeficiency virus type 1 (HIV-1), CTEs depend entirely on factors encoded by the host cell genome. We show that an RNA comprised almost entirely of the CTE of Mason-Pfizer monkey virus (CTE RNA) is exported efficiently from Xenopus oocyte nuclei. The CTE RNA and an RNA containing the RRE of HIV-1 (plus Rev) have little effect on export of one another, demonstrating differences in host cell requirements of these two viral mRNA export pathways. Surprisingly, even very low amounts of CTE RNA block export of normal mRNAs, apparently through the sequestration of cellular mRNA export factors. Export of a CTE-containing lariat occurs when wild-type CTE, but not a mutant form, is inserted into the pre-mRNA. The CTE has two symmetric structures, either of which supports export and the titration of mRNA export factors, but both of which are required for maximal inhibition of mRNA export. Two host proteins bind specifically to the CTE but not to non-functional variants, making these proteins candidates for the sequestered mRNA export factors.
Animals↗
Selection and nuclear immobilization of exportable RNAs.
The intracellular distribution of RNAs depends on interactions of cis-acting nuclear export elements or nuclear retention elements with trans-acting nuclear transport or retention factors. To learn about the relationship between export and retention, we isolated RNAs that are exported from nuclei of Xenopus laevis oocytes even when most RNA export is blocked by an inhibitor of Ran-dependent nucleocytoplasmic transport, the Matrix protein of vesicular stomatitis virus. Export of the selected RNAs is saturable and specific. When present in chimeric RNAs, the selected sequences acted like nuclear export elements in promoting efficient export of RNAs that otherwise are not exported; the pathway used for export of these chimeric RNAs is that used for the selected RNAs alone. However, these chimeric RNAs, unlike the selected RNAs, were not exported in the presence of Matrix protein; thus, the nonselected sequences can cause retention of the selected RNA sequences under conditions of impaired nucleocytoplasmic transport. We propose that most RNAs are transiently immobilized in the nucleus and that release of these RNAs is an essential and early step in export. Release correlates with functional Ran-dependent transport, and the lack of export of chimeric RNAs may result from interference with the Ran system.
Animals↗
In vivo selection of RNAs that localize in the nucleus.
Nuclear localization of an RNA is affected by cis-acting elements (NLEs) that lead to nuclear import or retention or to blockage of export from the nucleus. To identify such elements, we selected and analyzed transcripts that localized in the nuclei of Xenopus laevis oocytes. The RNAs were isolated from a collection of m7G-capped RNAs in which a combinatorial library (n = 20) of sequences had been inserted. One class of selected RNAs (Sm+) had a consensus Sm binding site (AAUUUUUGG) and bound Sm proteins in the cytoplasm; these RNAs resembled small nuclear RNAs like U1 and U5 RNAs in their bi-directional nucleocytoplasmic transport and their 5'-cap hypermethylation. Another class, Sm- RNAs, contained sequences that masked the m7G-caps of the RNAs and promoted interaction with La protein. These RNAs were retained within nuclei after nuclear injection and were imported when injected into the cytoplasm. Their nuclear import and retention were independent of a 5'-cap, required an imperfect double-stranded stem near the 5' end, and depended on interaction with La protein. Import of the Sm- RNAs, while using the import pathway of proteins, was distinct from that of U6 RNA.
Animals↗
Reproducibility and validity of electric source localisation with high-resolution electroencephalography.
The present study investigates the reproducibility and validity of the EEG source localisation of somatosensory evoked potentials (SEPs) using high-resolution EEG (61 scalp electrodes) and a source reconstruction on the basis of the individual brain morphology as obtained from magnetic resonance images (MRIs). The somatosensory evoked potentials (SEPs) to electrical stimulation of the right median nerve were repeatedly collected from the scalp of one healthy subject in 9 replications run on 9 different days. The source reconstruction for the 19 ms SEP component was performed by using a single moving dipole model as a source model. Two different head models were used: a spherical 3 shell model and a more realistically shaped 3 compartment model computed using the boundary element method (BEM). The source locations of the 19 ms SEP component were found to be highly reproducible using both head models: the mean standard deviation of the dipole locations was found to be 2.6 mm for the 3 shell model and 4 mm for the more realistically shaped head model. By projection into the individual MRI, the dipoles resulting from either head models were found to be located within the postcentral gyrus. The electric source locations were consistent with the maximum of the task-specific changes seen in a functional magnetic resonance imaging (fMRI) experiment when using the same somatosensory stimulation protocol.
Brain Mapping↗
Fungicidal activity of cecropin A.
Cecropin A (CA) fungicidal properties were explored. Nongerminated and germinated Aspergillus spp. and Fusarium spp. conidia were treated with CA. CA achieved complete lethality at < or = 25 microM (99 micrograms/ml) for germinating, but not nongerminating, conidia of Aspergillus spp. CA achieved total lethality for nongerminated and germinating conidia of Fusarium spp at 1.5 microM (6 micrograms/ml). MIC and minimal lethal concentration assays in buffered RPMI medium gave similar results.
Antifungal Agents↗