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S Thor

Publications and source records attributed to S Thor.

16 recordsLinked to original sources
PubMed2000

Chip is an essential cofactor for apterous in the regulation of axon guidance in Drosophila.

LIM-homeodomain transcription factors are expressed in subsets of neurons and are required for correct axon guidance and neurotransmitter identity. The LIM-homeodomain family member Apterous requires the LIM-binding protein Chip to execute patterned outgrowth of the Drosophila wing. To determine whether Chip is a general cofactor for diverse LIM-homeodomain functions in vivo, we studied its role in the embryonic nervous system. Loss-of-function Chip mutations cause defects in neurotransmitter production that mimic apterous and islet mutants. Chip is also required cell-autonomously by Apterous-expressing neurons for proper axon guidance, and requires both a homodimerization domain and a LIM interaction domain to function appropriately. Using a Chip/Apterous chimeric molecule lacking domains normally required for their interaction, we reconstituted the complex and rescued the axon guidance defects of apterous mutants, of Chip mutants and of embryos doubly mutant for both apterous and Chip. Our results indicate that Chip participates in a range of developmental programs controlled by LIM-homeodomain proteins and that a tetrameric complex comprising two Apterous molecules bridged by a Chip homodimer is the functional unit through which Apterous acts during neuronal differentiation.

Animals↗
PubMed1999

A LIM-homeodomain combinatorial code for motor-neuron pathway selection.

Different classes of vertebrate motor neuron that innervate distinct muscle targets express unique combinations of LIM-homeodomain transcription factors, suggesting that a combinatorial code of LIM-homeodomain proteins may underlie the control of motor-neuron pathway selection. Studies of LIM-homeodomain genes in mouse, Drosophila melanogaster and Caenorhabditis elegans have revealed functions of these genes in neuronal survival, axon guidance, neurotransmitter expression and neuronal function, but, to our knowledge, none of these studies have addressed the issue of a functional code. Here we study two members of this gene family in Drosophila, namely lim3, the homologue of the vertebrate Lhx3 and Lhx4 genes, and islet, the homologue of the vertebrate Isl1 and Is12 genes. We show that Drosophila lim3 is expressed by a specific subset of islet-expressing motor neurons and that mutating or misexpressing lim3 switches motor-neuron projections predictably. Our results provide evidence that lim3 and islet constitute a combinatorial code that generates distinct motor-neuron identities.

Amino Acid Sequence↗
PubMed1999

Chip and apterous physically interact to form a functional complex during Drosophila development.

LIM homeodomain (LIM-HD) proteins play key roles in a variety of developmental processes throughout the animal kingdom. Here we show that the LIM-binding protein Chip acts as a cofactor for the Drosophila LIM-HD family member Apterous (Ap) in wing development. We define the domains of Chip required for LIM-HD binding and for homodimerization and show that mutant proteins deleted for these domains act in a dominant-negative fashion to disrupt Ap function. Our results support a model for multimeric complexes containing Chip and Ap in transcriptional regulation. This model is confirmed by the activity of a chimeric fusion between Chip and Ap that reconstitutes the complex and rescues the ap mutant phenotype.

Animals↗
PubMed1998

Function and specificity of LIM domains in Drosophila nervous system and wing development.

LIM domains are found in a variety of proteins, including cytoplasmic and nuclear LIM-only proteins, LIM-homeodomain (LIM-HD) transcription factors and LIM-kinases. Although the ability of LIM domains to interact with other proteins has been clearly established in vitro and in cultured cells, their in vivo function is unknown. Here we use Drosophila to test the roles of the LIM domains of the LIM-HD family member Apterous (Ap) in wing and nervous system development. Using a rescuing assay of the ap mutant phenotype, we have found that the LIM domains are essential for Ap function. Furthermore, expression of LIM domains alone can act in a dominant-negative fashion to disrupt Ap function. The Ap LIM domains can be replaced by those of another family member to generate normal wing structure, but LIM domains are not interchangeable during axon pathfinding of the Ap neurons. This suggests that the Ap LIM domains mediate different protein interactions in different developmental processes, and that LIM domains can participate in conferring specificity of target gene selection.

Alleles↗
PubMed1998

Cell type-specific regulation of the Drosophila FMRF-NH2 neuropeptide gene by Apterous, a LIM homeodomain transcription factor.

We describe the direct and cell-specific regulation of the Drosophila FMRFa neuropeptide gene by Apterous, a LIM homeodomain transcription factor. dFMRFa and Apterous are expressed in partially overlapping subsets of neurons, including two of the seventeen dFMRFa cell types, the Tv neuroendocrine cells and the SP2 interneurons. Apterous contributes to the initiation of dFMRFa expression in Tv neurons, but not in those dFMRFa neurons that do not express Apterous. Apterous is not required for Tv neuron survival or morphological differentiation. Apterous contributes to the maintenance of dFMRFa expression by postembryonic Tv neurons, although the strength of its regulation is diminished. Apterous regulation of dFMRFa expression includes direct mechanisms, although ectopic Apterous does not induce ectopic dFMRFa. These findings show that, for a subset of neurons that share a common neurotransmitter phenotype, the Apterous LIM homeoprotein helps define neurotransmitter expression with very limited effects on other aspects of differentiation.

Animals↗
PubMed1997

Effect of pigmentation on the drug deposition in hair of grey-haired subjects.

The hair samples of 15 grizzled patients with a permanent medical treatment by amitriptyline, carbamazepine, chlorprothixene, diclofenac, doxepine, indomethacine, maprotiline or metoclopramide, or with a chronic heroin and cocaine abuse were separated into white and pigmented fibers and both fractions were independently investigated by GC-MS. The drugs were found in pigmented fibers as well as in white fibers, but the concentrations in the white fibers were smaller than in the pigmented ones for the most of the samples investigated. The concentration ratio of the drugs or their metabolites in both hair fractions (white/pigmented) was found to be between 0.09 and 1.57 (mean 0.70, 30 concentration pairs). There are large differences in this ratio between different subjects with the same drug, whereas for different drugs in the same subject in many cases similar ratios were measured. As a reason a different grade of pigmentation of the hair and the influence of the drug structure are discussed. From these results it follows that the natural hair colour is an important parameter in the evaluation of drug concentration in hair.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Structural and concentration effects on the deposition of tricyclic antidepressants in human hair.

In order to elucidate the possibility of a long-term compliance analysis the hair samples of 56 patients, who were under a permanent treatment with tricyclic antidepressants, were analyzed for amitriptyline, clomipramine, doxepine, imipramine and maprotiline as well as their nor-metabolites. The hair concentrations varied between 0.4 and 40 ng/mg with no strong difference between the five drugs. In comparison to the therapeutic plasma levels described in literature the nor-metabolites always accumulate less in hair than drugs. No correlation was found between the hair concentration and the daily dose. The investigation of the full hair length in 3-cm sections for several examples of all five drugs shows that they can be detected in normally kept hair at least 1 year after intake.

Adult↗
PubMed1997

The Drosophila islet gene governs axon pathfinding and neurotransmitter identity.

We have isolated the Drosophila homolog of the vertebrate islet-1 and islet-2 genes, two members of the LIM homeodomain family implicated in the transcriptional control of motor neuronal differentiation. Similar to vertebrates, Drosophila islet is expressed in a discrete subset of embryonic motor neurons and interneurons that includes the dopaminergic and serotonergic cells of the ventral nerve cord. In contrast to mouse where mutation of islet-1 leads to loss of neurons due to programmed cell death, Drosophila islet is not required for neuron survival. Instead, loss of islet function causes defects in axon pathfinding and targeting plus loss of dopamine and serotonin synthesis. Ectopic expression of islet induces both specific alterations in pathfinding and changes in neurotransmitter identity. These findings indicate that islet coordinately controls two distinct aspects of neuronal identity.

Animals↗
PubMed1995

Motoneuron fate specification revealed by patterned LIM homeobox gene expression in embryonic zebrafish.

In zebrafish, individual primary motoneurons can be uniquely identified by their characteristic cell body positions and axonal projection patterns. The fate of individual primary motoneurons remains plastic until just prior to axogenesis when they become committed to particular identities. We find that distinct primary motoneurons express particular combinations of LIM homeobox genes. Expression precedes axogenesis as well as commitment, suggesting that LIM homeobox genes may contribute to the specification of motoneuronal fates. By transplanting them to new spinal cord positions, we demonstrate that primary motoneurons can initiate a new program of LIM homeobox gene expression, as well as the morphological features appropriate for the new position. We conclude that the patterned distribution of different primary motoneuronal types within the zebrafish spinal cord follows the patterned expression of LIM homeobox genes, and that this reflects a highly resolved system of positional information controlling gene transcription.

Amino Acid Sequence↗
PubMed1995

Control of neuronal pathway selection by the Drosophila LIM homeodomain gene apterous.

The Drosophila apterous gene encodes a LIM homeodomain protein expressed embryonically in a small subset of differentiating neurons. To establish the identity of these neurons and to study the role of apterous in their development, we made apterous promoter fusions to an axon-targeted reporter gene. We found that all apterous-expressing neurons are interneurons that choose a single pathway within the developing central nervous system. In apterous mutants, these neurons choose incorrect pathways and fail to fasciculate with one another. Our results indicate that apterous functions to control neuronal pathway selection and suggest that other vertebrate and invertebrate members of the LIM homeodomain class of proteins may serve similar functions.

Animals↗
PubMed1993

Zebrafish primary neurons initiate expression of the LIM homeodomain protein Isl-1 at the end of gastrulation.

Isl-1 has previously been established as the earliest marker of developing chicken spinal motor neurons where it is regulated by inductive signals from the floorplate and notochord. We now report that, in zebrafish, the expression of Isl-1 is initiated in Rohon-Beard cells, primary motor neurons, interneurons and cranial ganglia, hours before the neural tube itself is formed. The expression is initiated simultaneously in the Rohon-Beard cells and the primary motor neurons, at the axial level of the presumptive first somite. The Isl-1-expressing motor neurons appear on either side of the ventral midline whereas the interneurons and Rohon-Beard cells initiate expression while located at the edge of the germinal shield. Isl-1 expression is initiated in these cells before the formation of a differentiated notochord. Isl-1 is expressed in the various functional classes of primary neurons at 24 hours postfertilization. This selective expression of a homeodomain protein in the primary neurons implies that these neurons share a common program of early development and that they have evolved and been selected for as a coordinated system. One of the functions of the primary neurons is to send long axons which pioneer the major axon tracts in the zebrafish embryo. An evolutionary conserved functional role for Isl-1 in the expression of the pioneering phenotype of the primary neurons is suggested.

Animals↗
PubMed1992

Early stages of motor neuron differentiation revealed by expression of homeobox gene Islet-1.

Motor neurons in the embryonic chick spinal cord express a homeobox gene, Islet-1, soon after their final mitotic division and before the appearance of other differentiated motor neuron properties. The expression of Islet-1 by neural cells is regulated by inductive signals from the floor plate and notochord. These results establish Islet-1 as the earliest marker of developing motor neurons. The molecular nature of the Islet-1 protein suggests that it may be involved in the establishment of motor neuron fate.

Animals↗
PubMed1991

The homeodomain LIM protein Isl-1 is expressed in subsets of neurons and endocrine cells in the adult rat.

We have used immunocytochemical methods to localize the homeodomain LIM protein Isl-1 in the adult rat. Isl-1 immunoreactivity is expressed in polypeptide hormone-producing cells of the endocrine system, in neurons of the peripheral nervous system, and in a subset of brain nuclei. Isl-1 is also expressed in a subset of motoneurons in the spinal cord and brain stem, but not in regions of the central nervous system involved in sensory function or in neocortical areas. The pattern of expression of Isl-1 suggests that this gene may be involved in the specification and maintenance of differentiated phenotypical properties of these cells.

Animals↗
PubMed1991

Novel insulin promoter- and enhancer-binding proteins that discriminate between pancreatic alpha- and beta-cells.

In the mouse insulin is first detected on embryonic day 12 (e12) in a subpopulation of the cells that on e10 start to produce glucagon. During the continued embryonic development, the number of cells that coexpress the two hormones is gradually decreased, and in adults the expression of these two hormone genes is segregated to the beta- and alpha-cells. To begin to understand the process of terminal differentiation that restricts insulin gene expression to beta-cells, we have assayed for the presence of nuclear proteins that interact with transcriptional regulatory sequences of the rat insulin I gene in pancreatic alpha- and beta-cell lines. All except one of the previously identified insulin enhancer-binding proteins were found to be present in both cell types. A new insulin promoter-binding protein, IPF1, which was present in beta-cells but absent in alpha-cells, was identified. The beta-cell specificity of IPF1 implies that the insulin promoter is involved in the restriction of insulin gene expression to the beta-cells. The binding sites for IPF1 and the beta-cell-specific enhancer-binding protein IEF2 are both recognized by the previously isolated homeodomain-containing LIM protein isl-1, but these three proteins were all shown to be different entities.

Animals↗
PubMed1990

Insulin gene enhancer binding protein Isl-1 is a member of a novel class of proteins containing both a homeo- and a Cys-His domain.

The activity of the rat insulin I gene enhancer is mainly dependent on two cis-acting protein-binding domains. Here we report the isolation of a complementary DNA encoding a protein, Isl-1, that binds to one of these domains. Isl-1 contains a homeodomain with greatest similarity to those of the Caenorhabditis elegans proteins encoded by mec-3 and lin-11. In addition, Isl-1, like the lin-11 and mec-3 gene products, contains a novel Cys-His domain which is reminiscent of known metal-binding regions. Together these proteins define a novel class of proteins containing both a homeo- and a Cys His-domain. Isl-1 is preferentially expressed in cells of pancreatic endocrine origin. If the structural homologies between Isl-1 and the C. elegans gene products reflect functional similarities, a role for Isl-1 in the development of pancreatic endocrine cells could be envisaged.

Amino Acid Sequence↗