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.
Numerical and spatial cognition rely on common functional circuits in the parietal lobes of the brain
1. While previous work has established that the mere perception of numbers can bias a subject's ...attention in space
2, the method of random digit generation has only recently been introduced to a rapidly growing literature exploring asymmetries in number space
3. Here we show that human subjects' attempts to generate numbers ‘at random’ are systematically influenced by lateral head turns, which are known to reallocate spatial attention in the outside world. Specifically, while facing left, subjects produced relatively small numbers, whereas while facing right they tended to produce larger numbers. These results support current concepts of parietal cortex as mediating the interplay between spatial attention and abstract thought
4.
Valerian extracts have been used for centuries to alleviate restlessness and anxiety albeit with unknown mechanism of action in vivo. We now describe a specific binding site on GABA(A) receptors with ...nM affinity for valerenic acid and valerenol, common constituents of valerian. Both agents enhanced the response to GABA at multiple types of recombinant GABA(A) receptors. A point mutation in the beta2 or beta3 subunit (N265M) of recombinant receptors strongly reduced the drug response. In vivo, valerenic acid and valerenol exerted anxiolytic activity with high potencies in the elevated plus maze and the light/dark choice test in wild type mice. In beta3 (N265M) point-mutated mice the anxiolytic activity of valerenic acid was absent. Thus, neurons expressing beta3 containing GABA(A) receptors are a major cellular substrate for the anxiolytic action of valerian extracts.
Productive symptoms of schizophrenia and positive-symptom schizotypy have both been related to signs of right-sided hemispatial inattention ("pseudoneglect"). We here set out to explore, in healthy ...subjects, the relationship between one form of mild schizotypy ("magical ideation"; MI) and asymmetries in number space, which is a bias toward relatively small numbers, reportedly represented to the left of larger numbers.
Forty right-handed participants filled in the MI scale and performed a number-line bisection (NLB) task and a randomization task (the Mental Dice Task, MDT, requiring randomization of the digits from 1 to 6).
We found pseudoneglect in number space, that is, more errors toward small numbers in the NLB task and an overproduction of small digits in the MDT. Individual participants' MI scores were correlated to the size of pseudoneglect in both numerical tasks.
Explicit (NLB) and implicit (MDT) assessments of the exploration of number space may be relevant to studies of the mechanisms underlying the formation of delusional and schizotypal beliefs. We propose that, in healthy subjects, a trait-like imbalance in hemispheric cooperation may not only produce asymmetries in physical and representational space, but also predisposes to develop magical ideas. Specifically, an over-proportional influence of the right hemisphere semantic system (preferentially coding oblique and remote associations) leads to the assumption of connections between randomly associated events.
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.
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, usp3and usp4, 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, usp2, 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.
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.
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 supernumerary 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.
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.
The steroid hormone 20-hydroxyecdysone induces metamorphosis in insects. The receptor for the hormone is the ecdysone receptor, a heterodimer of two nuclear receptors, EcR and USP. In
Drosophila the
...EcR gene encodes 3 isoforms (EcR-A, EcR-B1 and EcR-B2) that vary in their N-terminal region but not in their DNA binding and ligand binding domains. The stage and tissue specific distribution of the isoforms during metamorphosis suggests distinct functions for the different isoforms. By over-expressing the three isoforms in animals we present results supporting this hypothesis. We tested for the ability of the different isoforms to rescue the lack of dendritic pruning that is characteristic of mutants lacking both EcR-B1 and EcR-B2. By expressing the different isoforms specifically in the affected neurons, we found that both EcR-B isoforms were able to rescue the neuronal defect cell autonomously, but that EcR-A was less effective. We also analyzed the effect of over-expressing the isoforms in a wild-type background. We determined a sensitive period when high levels of either EcR-B isoform were lethal, indicating that the low levels of EcR-B at this time are crucial to ensure normal development. Over-expressing EcR-A in contrast had no detrimental effect. However, high levels of EcR-A expressed in the posterior compartment suppressed puparial tanning, and resulted in down-regulation of some of the tested target genes in the posterior compartment of the wing disc. EcR-B1 or EcR-B2 over-expression had little or no effect.
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