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 ( )-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.
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.
Loss of function of either the ecdysone receptor (EcR) or Ultraspiracle (USP), the two components of the ecdysone receptor, causes precocious differentiation of the sensory neurons on the wing of ...Drosophila. We propose that the unliganded receptor complex is repressive and that this repression is relieved as the hormone titers increase at the onset of metamorphosis. The point in development where the receptor complex exerts this repression varies for different groups of sensilla. For the chemosensory organ precursors along the wing margin, the block is at the level of senseless expression and is indirect, via the repressive control of broad expression. Misexpressing broad or senseless can circumvent the repression by the unliganded receptor and leads to precocious differentiation of the sensory neurons. This precocious differentiation results in the misguidance of their axons. The sensory precursors of some of the campaniform sensilla on the third longitudinal vein are born prior to the rise in ecdysone. Their differentiation is also repressed by the unliganded EcR/USP complex but the block occurs after senseless expression but before the precursors undertake their first division. We suggest that in imaginal discs the unliganded EcR/USP complex acts as a ligand-sensitive ;gate' that can be imposed at various points in a developmental pathway, depending on the nature of the cells involved. In this way, the ecdysone signal can function as a developmental timer coordinating development within the imaginal disc.
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.
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