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M Schubiger

Publications and source records attributed to M Schubiger.

17 recordsLinked to original sources
PubMed2001

The dual role of ultraspiracle, the Drosophila retinoid X receptor, in the ecdysone response.

The Drosophila homolog of the retinoid X receptor, ultraspiracle (USP), heterodimerizes with the ecdysone receptor (EcR) to form a functional complex that mediates the effects of the steroid molting hormone ecdysone by activating and repressing expression of ecdysone response genes. As with other retinoid X receptor heterodimers, EcR/USP affects gene transcription in a ligand-modulated manner. We used in vivo, cell culture, and biochemical approaches to analyze the functions of two usp alleles, usp(3) and usp(4), which encode stable proteins with defective DNA-binding domains. We observed that USP is able to activate as well as repress the Z1 isoform of the ecdysone-responsive broad complex (BrC-Z1). Activation of BrC-Z1 as well as EcR, itself an ecdysone response gene, can be mediated by both the USP3 and USP4 mutant proteins. USP3 and USP4 also activate an ecdysone-responsive element, hsp27EcRE, in cultured cells. These results differ from the protein null allele, usp(2), which is unable to mediate activation [Schubiger, M. & Truman, J. W. (2000) Development 127, 1151--1159]. BrC-Z1 repression is compromised in all three usp alleles, suggesting that repression involves the association of USP with DNA. Our results distinguish two mechanisms by which USP modulates the properties of EcR: one that involves the USP DNA-binding domain and one that can be achieved solely through the ligand-binding domain. These newly revealed properties of USP might implicate similar properties for retinoid X receptor.

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PubMed2000

The RXR ortholog USP suppresses early metamorphic processes in Drosophila in the absence of ecdysteroids.

The steroid hormone 20-hydroxyecdysone (20E) initiates metamorphosis in insects by signaling through the ecdysone receptor complex, a heterodimer of the ecdysone receptor (EcR) and ultraspiracle (USP). Analysis of usp mutant clones in the wing disc of Drosophila shows that in the absence of USP, early hormone responsive genes such as EcR, DHR3 and E75B fail to up-regulate in response to 20E, but other genes that are normally expressed later, such as (&bgr;)-Ftz-F1 and the Z1 isoform of the Broad-Complex (BRC-Z1), are expressed precociously. Sensory neuron formation and axonal outgrowth, two early metamorphic events, also occur prematurely. In vitro experiments with cultured wing discs showed that BRC-Z1 expression and early metamorphic development are rendered steroid-independent in the usp mutant clones. These results are consistent with a model in which these latter processes are induced by a signal arising during the middle of the last larval stage but suppressed by the unliganded EcR/USP complex. Our observations suggest that silencing by the unliganded EcR/USP receptor and the subsequent release of silencing by moderate steroid levels may play an important role in coordinating early phases of steroid driven development.

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PubMed1998

Drosophila EcR-B ecdysone receptor isoforms are required for larval molting and for neuron remodeling during metamorphosis.

During the metamorphic reorganization of the insect central nervous system, the steroid hormone 20-hydroxyecdysone induces a wide spectrum of cellular responses including neuronal proliferation, maturation, cell death and the remodeling of larval neurons into their adult forms. In Drosophila, expression of specific ecdysone receptor (EcR) isoforms has been correlated with particular responses, suggesting that different EcR isoforms may govern distinct steroid-induced responses in these cells. We have used imprecise excision of a P element to create EcR deletion mutants that remove the EcR-B promoter and therefore should lack EcR-B1 and EcR-B2 expression but retain EcR-A expression. Most of these EcR-B mutant animals show defects in larval molting, arresting at the boundaries between the three larval stages, while a smaller percentage of EcR-B mutants survive into the early stages of metamorphosis. Remodeling of larval neurons at metamorphosis begins with the pruning back of larval-specific dendrites and occurs as these cells are expressing high levels of EcR-B1 and little EcR-A. This pruning response is blocked in the EcR-B mutants despite the fact that adult-specific neurons, which normally express only EcR-A, can progress in their development. These observations support the hypothesis that different EcR isoforms control cell-type-specific responses during remodeling of the nervous system at metamorphosis.

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PubMed1994

A mutation of the Drosophila sodium pump alpha subunit gene results in bang-sensitive paralysis.

A bang-sensitive enhancer trap line was isolated in a behavioral screen. The flies show a weak bang-sensitive paralysis, recovering after about 7 s. The P element insert is localized at 93B1-2 on the salivary chromosomes, the site of the (Na+,K+)ATPase alpha subunit gene. Molecular characterization demonstrates that the transposon is inserted into the first intron of this gene. This insertion leads to normal-sized transcripts, but reduced levels of expression. This change is also reflected in lower amounts of a normal-sized alpha subunit protein. Mutant flies show a much greater sensitivity to ouabain, likewise indicating, on a functional level, a reduction in Na+ pump activity. Furthermore, the bang-sensitive behavior can also be mimicked by injecting sublethal doses of ouabain into wild-type flies. The molecular and functional evidence indicates that the insertion has produced a hypomorphic mutation of the (Na+,K+)ATPase alpha subunit gene, opening the way to future studies of the regulation of the Na+ pump.

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PubMed1990

Neurogenic and antineurogenic effects from modifications at the Notch locus.

The best studied mutations at the Notch locus produce a neurogenic phenotype, with a massive overgrowth of the nervous system at the expense of epidermis. We report here that, in the development of the adult peripheral nervous system, the Abruptex alleles of Notch have the opposite phenotype, namely an underproduction of sensory organs or sensilla. This arises primarily not from an arrest of the lineages that produce sensilla, from the degeneration of sensillar cells, or from the transformation into neurons of cells that normally secrete the cuticular components of a sensillum (as can happen in Notch alleles). Rather, our evidence argues strongly that the sensillar mother cells never form. This implies that the Notch protein plays a role in the process that first generates a difference between sensillar mother cells and ordinary epidermal cells. The number of sensilla formed on the wing of flies carrying multiple doses of Notch+ is virtually the same as that of wild type, i.e. the Abruptex phenotype is not reproduced to any significant extent. This suggests that the single amino acid substitutions that occur in Abruptex mutants confer on the protein some functionally distinctive feature, possibly more powerful intermolecular binding or altered stability.

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PubMed1987

Changing spatial patterns of DNA replication in the developing wing of Drosophila.

Using an antibody against bromodeoxyuridine we have analyzed the distribution of S-phase nuclei in the wing disc of Drosophila as the larval disc transforms into the adult wing during metamorphosis. On the basis of the timing of replication three cell populations can be distinguished: the cells of the presumptive wing margin, the precursor cells of the longitudinal veins, and those of the intervein regions. In each of these populations the cell cycle is first arrested and later resumes at a specific time, so that at each developmental time point a characteristic spatial pattern of S-phase nuclei is seen. An interpretation of these changing patterns in terms of vein formation, compartments, and neural development is offered.

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PubMed1986

Axonal polarity in Drosophila wings with mutant cuticular polarity patterns.

In Drosophila melanogaster certain mutations alter the polarity of trichomes and bristles, cuticular structures secreted by the epithelial cells of the adult fly. Since sensory neurons arise from epithelial cell precursors, and sensory axons grow along the inner faces of epithelial cells, we have studied the developing wings of these mutants to see whether the change in epithelial cell polarity has an influence on the direction of axon outgrowth. The nerve patterns formed in the mutants prickled, inturned, and frizzled, however, were largely normal, indicating that in these cases the polarity of the cuticular structures produced by the epithelial cells is altered without any effect on the polarity of the associated axons.

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PubMed1985

Genetic suppression of putative guidepost cells: effect on establishment of nerve pathways in Drosophila wings.

In the developing wing of Drosophila a set of early differentiating neurons pioneer the axon courses observed in the adult. The possibility that these first cells are indispensable for establishing the normal neural pathways has been tested. The differentiation of particular neurons was suppressed by inducing cell clones homozygous for two scute deficiencies, mutations that inhibit the differentiation of sensilla and their associated neurons. From the analysis of the nerve patterns in wings lacking specific sensilla, it has been demonstrated that none of the identified neurons are essential for guiding other axons along the correct path. However, the possibility remains that the presence of certain cells may increase the probability of establishing the normal pattern of peripheral nerves.

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PubMed1984

Neuron differentiation and axon growth in the developing wing of Drosophila melanogaster.

Sensory neurons in the wing of Drosophila originate locally from epithelial cells and send their axons toward the base of the wing in two major bundles, the L1 and L3 nerves. We have estimated the birth times of a number of identified wing sensory neurons using an X-irradiation technique and have followed the appearance of their somata and axons by means of an immunohistochemical stain. These cells become immunoreactive and begin axon growth in a sequence which mirrors the sequence of their birth times. The earliest ones are born before pupariation and begin axonogenesis within 1 to 2 hr after the onset of metamorphosis; the last are born and differentiate some 12 to 14 hr later. The L1 and L3 nerves are formed in sections, with specific neurons pioneering defined stretches of the pathways during the period between 0 and 4 hr after pupariation (AP), and finally joining together around 12 hr AP. By 16 hr AP the adult complement of neurons is present and the adult peripheral nerve pattern has been established. Pathway establishment appears to be specified by multiple cues. In places where neurons differentiate in close proximity to one another, random filopodial exploration followed by axon growth to a neighboring neuron soma might be the major factor leading to pathway construction. In other locations, filopodial contact between neighboring somata does not appear to occur, and axon pathways joining neural neighbors by the most direct route are not established. We propose that in these cases additional factors, including veins which are already present at the time of axonogenesis, influence the growth of axons through non-neural tissues.

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PubMed1983

The polarity of axon growth in the wings of Drosophila melanogaster.

We have analyzed the growth of axons in the wings of the mutants Hairy wing and hairy of Drosophila melanogaster. These mutants produce many supernumerary bristle organs and sensilla campaniformia, whose axons grow between the two wing epithelia and can be visualized in both pupal and adult stages. The sensory axons of wild-type animals follow two paths in the wing, within longitudinal veins L1 and L3, and always grow with a distal to proximal polarity. In the mutants, all axons following these two paths likewise grow with correct polarity. Axons elsewhere in the wing, however, are found to grow in many different directions, including from proximal to distal and hence directly away from the central nervous system. A variety of patterns of axon growth and fasciculation are seen in different individuals. Only if the supernumerary axons encounter the two normal paths do they reliably grow toward the base of the wing. We conclude that these two paths provide polarity information for axon growth, information which is either not used or not available elsewhere in the wing in spite of the obvious morphological polarization of every epithelial cell. The time course of neural differentiation suggests that the normal sensory cells of mutant wings, which grow axons relatively early, may be the source of polarity information for the later-differentiating supernumerary cells.

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PubMed1975

Phenogenetics of the eyeless-dominant mutant of Drosophila melanogaster.

The eyeless-Dominant (eyD) mutation is a fourth chromosome insertional translocation which affects the eyes, antennae, ocelli, and sexcombs when heterozygous but is a larval-pupal lethal when homozygous. By use of a crowding technique, it was possible to separate eyD homozygotes and heterozygotes with 100% accuracy at an early stage of larval development. Under these conditions, the eyD homozygotes had a biphasic lethal period since 45% died as first or second instar larvae and 55% died as pupae. The eyDleyD pupal lethal, isolated by this technique, was able to form all the adult structures with the exception of the eye-antennal disc derivatives. The brain was present but abnormal. In testing the competence of the eyDleyD larval eye discs by means of transplantation experiments, it has been demonstrated that the mutant discs develop non-autonomously. Histological studies have revealed the existence of neurological defects in both eyD heterozygotes and homozygotes. The eyDleyD lethal larvae lacked detectable optic formation centers and showed an extreme reduction in the number of cells present in the cortex of the brain. The ey"dleyD lethal pupae possessed partial formation centers and also had severe reduction in the number of cortical cells. The eyD heterozygotes possessed normal appearing formation centers but they did exhibit a moderate reduction in the number of their cortical cells as compared to wild-type. These studies have shown that there is a direct correlation between the extent of neurological damage and the time of developmental arrest. It appears that the eyD mutation must adversely affect the neuroblasts at a very early stage of development. As a working hypothesis, it is suggested that the eyD mutation operates via the same basic mechanism of cell death in heterozygous and homozygous animals.

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PubMed1975

Central connections of receptors on rotated and exchanged cerci of crickets.

The cerci of crickets, paired abdominal appendages bearing sound-sensitive filiform hairs, can be removed and grafted back so that their morphological axes acquire various relationships to those of the body. We have studied both the morphogenetic consequences of such surgery and the central connections made by the regenerating axons of the cercal sensory neurons. If a cercus is rotated and grafted back into its own socket, it back-rotates towards its original orientation in succeeding molts. If left and right cerci are exchanged, with or without rotation, back-rotation does not occur and super-numerary cerci are formed in predictable locations. There are two sub-populations of filiform hairs: those that vibrate transversely to the cercal shaft (T-hairs) in dorsal and ventral sectors, and longitudinally vibrating hairs (L-hairs) in lateral and medial sectors. Two giant interneurons are excited by T-hairs of their own side but not by L-hairs. If cerci are grafted so that they assume various orientations relative to the body, a consistent physiological result is obtained: T-hairs always appear to be the source of excitatory input to the giant interneurons, no matter where they are caused to be located by prior surgery. The phenomena of back-rotation, formation of supernumerary cerci, and formation of connections selectively by T-hairs, can be interpreted on the hypothesis of morphogenetic gradients.

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