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Temporal and spatial expression of homeotic genes is important for segment-specific neuroblast 6-4 lineage formation in Drosophila.

Different proliferation of neuroblast 6-4 (NB6-4) in the thorax and abdomen produces segmental specific expression pattern of several neuroblast marker genes. NB6-4 is divided to form four medialmost cell body glia (MM-CBG) per segment in thorax and two MM-CBG per segment in abdomen. As homeotic genes determine the identities of embryonic segments along theA/P axis, we investigated if temporal and specific expression of homeotic genes affects MM-CBG patterns in thorax and abdomen. A Ubx loss-of-function mutation was found to hardly affect MM-CBG formation, whereas abd-A and Abd-B caused the transformation of abdominal MM-CBG to their thoracic counterparts. On the other hand, gain-of-function mutants of Ubx, abd-A and Abd-B genes reduced the number of thoracic MM-CBG, indicating that thoracic MM-CBG resembled abdominal MM-CBG. However, mutations in Polycomb group (PcG) genes, which are negative transregulators of homeotic genes, did not cause the thoracic to abdominal MM-CBG pattern transformation although the number of MM-CBG in a few per-cent of embryos were partially reduced or abnormally patterned. Our results indicate that temporal and spa-tial expression of the homeotic genes is important to determine segmental-specificity of NB6-4 daughter cells along the anterior-posterior (A/P) axis.

Abdomen↗

The olfactory bulb as an independent developmental domain.

The olfactory system is a good model to study the mechanisms underlying guidance of growing axons to their appropriate targets. The formation of the olfactory bulb involves differentiation of several populations of cells and the initiation of the central projections, all under the temporal and spatial patterns of gene expression. Moreover, the nature of interactions between the olfactory epithelium, olfactory bulb and olfactory cortex at early developmental stages is currently of great interest. To explore these questions more fully, the present review aims to correlate recent data from different developmental studies, to gain insight into the mechanisms involved in the specification and development of the olfactory system. From our studies in the pax6 mutant mice (Sey(Neu)/Sey(Neu)), it was concluded that the initial establishment of the olfactory bulb central projections is able to proceed independently of the olfactory sensory axons from the olfactory epithelium. The challenge that now remains is to consider the validity of the olfactory bulb as an independent development domain. In the course of evaluating these ideas, we will review the orchestra of molecular cues involved in the formation of the projection from the OB to the olfactory cortex.

Animals↗

Non-overlapping expression of CRBP I and CRABP I during pattern formation of limbs and craniofacial structures in the early mouse embryo.

Retinoic acid (RA), a physiological metabolite of retinol (vitamin A), is thought to be of importance for pattern formation in the developing embryo. However, the mechanism by which RA is generated, as well as the site of its formation in the developing embryo, is still unknown. In this paper, we show that radiolabelled retinol, administered to pregnant mice, is accumulated in specific locations in the embryos. As revealed by immunohistochemistry using antibodies to cellular retinol-binding protein I (CRBP I), retinol accumulates in regions of the embryo expressing CRBP I. In limbs and craniofacial structures, CRBP I expression and retinol accumulation was seen in endoderm and surface ectoderm. Most mesenchymal cells of the limbs and craniofacial structures did not express detectable levels of CRBP I but instead expressed cellular retinoic acid-binding protein I (CRABP I). Previous results have demonstrated that CRABP I is involved in accumulation of RA in the embryo. Thus, the spatially closely related but non-overlapping domains of expression of CRBP I and CRABP I suggests a role of a retinol/RA pathway in epithelial-mesenchymal interactions during pattern formation of limbs and of craniofacial structures.

Animals↗

Pattern formation in a patch occupancy metapopulation model: a cellular automata approach.

The explicit consideration of space in ecological research is of paramount importance to understand the structure and functioning of ecological systems. In this paper we develop a simple spatially explicit metapopulation model in which colonization is constant and independent of the number of occupied patches (i.e. propagule-rain effect, Gotelli, 1991). Extinction, on the other hand, is modelled as a stochastic process whose intensity depends on the number of occupied patches in the neighborhood of each focal patch. Our model is the CA counterpart of two classical patch occupancy metapopulation models. We analytically prove this by showing that our CA converges to the differential equation in the mean-field approximation. The asymptotic behaviour of the system, expressed as the proportion of occupied patches, agrees with the equilibrium proportion of patches derived by using ODEs. In both models, the existence of a rescue-effect increases the range of extinction and colonization parameters over which the system attains complete occupancy of patches. However, in our model this result is strongly influenced by the degree of coupling among patches and is apparent only for local interactions. With local interactions and particular parameter values of colonization and extinction, self-organized spatio-temporal patterns emerge with a fractal-like clustering, even though the environment is spatially homogeneous. Our results point out that the importance of being spatial and discrete (Durrett & Levin, 1994a) in our model is a result of local interactions.

Ecology↗

Spatial working memory in Asperger's syndrome and in patients with focal frontal and temporal lobe lesions.

Spatial working memory (SWM) was investigated in 15 patients with Asperger's syndrome (AS) comparing their performance to 18 age- and IQ-matched control subjects. An additional comparison was made with 20 unilateral frontal excision patients [9 right (RFL); 11 left (LFL)] and with 38 unilateral temporal lobectomy patients [18 right (RTL); 18 left (LTL)], the frontal and temporal lobe patients having separate matched control groups. SWM was tested using the Executive Golf Task, a test that also measures spatial strategy formation. The AS group showed a substantial deficit on SWM, but no impairment in strategy formation. The LFL showed the same pattern of impairment, but with a less substantial deficit. The RFL group showed a large deficit, but some of this was accounted for by a strategy formation impairment. Of the temporal lobe lesions groups, only the RTL group was impaired on SWM, but this group showed normal strategy formation. It was concluded that the SWM deficit in AS may reflect a more general difficulty in accessing different types of representations in order to guide voluntary behavior, providing at least a partial explanation for the executive deficits found in AS.

Adolescent↗

Cell fates in the adult abdomen of Drosophila are determined by wingless during pupal development.

wingless activity is required for the patterning of tergites and sternites in the adult abdomen of Drosophila melanogaster. In the absence of wg, tergite and sternite cuticular differentiation is replaced by that of pleura. Temperature shift analysis of a wg temperature-sensitive allele has shown that sensory bristles and tergite/sternite histotype are determined independently and that wg is required between 15 and 20 hr after pupariation for bristle formation. The determination of sensory mother cells at this stage of development was confirmed by expression of the neuralized gene in a subset of the proliferating histoblasts. Ectopic expression of wg leads to the appearance of ectopic bristles and expanded tergite and sternite, indicating that wg expression is sufficient to promote both bristle formation and tergite/sternite differentiation. wg is expressed in the dividing and spreading histoblast population in a restricted pattern which may determine the spatial arrangement of cuticular elements.

Abdomen↗

Rapid evolution of a recently retroposed transcription factor YY2 in mammalian genomes.

YY2 was originally identified due to its unusual similarity to the evolutionarily well-conserved zinc finger gene YY1. In this study, we have determined the evolutionary origin and conservation of YY2 using comparative genomic approaches. Our results indicate that YY2 is a retroposed copy of YY1 that has been inserted into another gene locus named Mbtps2 (membrane-bound transcription factor protease site 2). This retroposition is estimated to have occurred after the divergence of placental mammals from other vertebrates based on the detection of YY2 only in the placental mammals. The N- and C-terminal regions of YY2 have evolved under different selection pressures. The N-terminal region has evolved at a very fast pace with very limited functional constraints, whereas the DNA-binding, C-terminal region still maintains a sequence structure very similar to that of YY1 and is also well conserved among placental mammals. In situ hybridizations using different adult mouse tissues indicate that mouse YY2 is expressed at relatively low levels in Purkinje and granular cells of cerebellum and in neuronal cells of cerebrum, but at very high levels in testis. The expression levels of YY2 are much lower than those of YY1, but the overall spatial expression patterns are similar to those of Mbtps2, suggesting a possible shared transcriptional control between YY2 and Mbtps2. Taken together, the formation and evolution of YY2 represent a very unusual case where a transcription factor was first retroposed into another gene locus encoding a protease and survived with different selection schemes and expression patterns.

Amino Acid Sequence↗

A PDZ-binding motif as a critical determinant of Rho guanine exchange factor function and cell phenotype.

We identified a Rho guanine exchange factor (GEF) expressed as two splice variants, which differ only in either having or lacking a Postsynaptic density 95, Disk large, Zona occludens-1 (PDZ) motif. The PDZ adaptor protein synectin bound the longer splice variant, Syx1, which was targeted to the plasma membrane in a synectin-dependent manner. The shorter variant, Syx2, was diffusely distributed in the cytoplasm. Fluorescence resonance energy transfer (FRET) imaging revealed similar differences between the spatial patterns of active RhoA in Syx1 versus Syx2-expressing cells. Expression of Syx1 augmented endothelial cell (EC) migration and tube formation, whereas Syx2 expression did not. It appears, therefore, that synectin-dependent targeting of Syx is critical to its contribution to these EC functions. Although agonist-stimulated global RhoA activity was similar in Syx1- and Syx2-expressing cells, basal RhoA activity was surprisingly higher in the latter. Out of 23 cell types, we found a significant level of endogenous Syx2 expression only in brain tumor cells, which also exhibited high basal RhoA activity. We found that the activity level of JNK, which mediates transcriptional regulation downstream of RhoA, is elevated in a Syx2-dependent manner in these cells, possibly contributing to their tumorigenicity.

Adaptor Proteins, Signal Transducing↗

The generalized convulsive seizure state induced by daily electrical stimulation of the amygdala in split brain cats.

Daily unilateral electrical stimulation of amygdala in forebrain bisected cats provoked the development of the final stage of the kindled convulsion with remarkable rapidity regardless of presence or absence of anterior commissure. The chronological and spatial pattern of propagation of afterdischarge, interictal spike discharge, and clinical manifestations strongly suggest the significant role played by the midbrain reticular formation and possibly other brainstem structures in the progressive electroclinical seizure development. This assumption was supported by the results of a lesion study in which placement of a destructive lesion in the ipsilateral midbrain reticular formation markedly increased the generalized seizure triggering threshold, lateralized the afterdischarge to the stimulated hemisphere when induced with increased intensity stimulation, fragmented clinical seizure manifestations, and failed to produce progression of clinical and electrographic events with prolonged daily stimulation. This is in contrast to the insignificant effect produced by a peduncular lesion. Our findings suggest that vertical (limbic-brainstem), but not horizontal (transhemispheric interlimbic) connection is critically involved in the amygdaloid seizure development while the forebrain commissures may play a role in the development of bisynchronous and bisymmetrical ictal and interictal electrographic and clinical manifestations. Finally, possible differential effect of forebrain bisection depending on developing in contrast with a established (cerebral) hemispheric epileptogenic process is postulated to explain the "facilitatory" effect observed in our series in contrast to the beneficial effects reported on some intractable seizure patients.

Amygdala↗

ERECT WING, the Drosophila member of a family of DNA binding proteins is required in imaginal myoblasts for flight muscle development.

The erect wing locus of the fruit fly Drosophila melanogaster encodes a protein, EWG, that shares extensive homology with the P3A2 DNA binding protein of sea urchin and a recently identified mammalian transcription factor. Loss-of-function erect wing alleles result in embryonic lethality. Viable alleles of erect wing cause severe abnormalities of the indirect flight muscles. We have analyzed the spatial pattern of erect wing expression in the developing indirect flight muscles during postembryonic development. EWG is detected, 10 hours after puparium formation, in myoblasts that will form the indirect flight muscles. The early events of muscle development are normal in ewg mutants. However, a few hours after the onset of erect wing expression in myoblasts, defects are seen in the developing indirect flight muscles which subsequently degenerate. We present results that show that the normal development of the indirect flight muscles requires erect wing expression in the progenitor myoblasts themselves. Finally, we examine the role of target muscles in the arborization of motor axons by studying the developing innervation to the flight muscle in erect wing mutants. Our study demonstrates, for the first time, a role for a regulatory gene expressed in imaginal myoblasts in Drosophila.

Animals↗

The molecular basis of pattern formation in the developing compound eye of Drosophila.

Throughout metazoan development cells select pathways of specialization that lead to the differentiation of specific cell types. Differential gene activation converts initially homogeneous populations of cells into spatial arrangements of diverse cell types. As discussed in other articles in this issue, the signals specifying divergent pathways can be encoded in a cell's lineage, its environment, or a combination of both. This article reviews recent analyses of the developing Drosophila compound eye which have focussed upon the mechanisms by which cells assess environmental information in order to determine their fate. More specifically, it examines the molecular mechanisms used by cells to communicate signals which instruct the developmental pathways of other cells.

Animals↗

Possible roles for stanniocalcin during early skeletal patterning and joint formation in the mouse.

Stanniocalcin (STC) is a polypeptide hormone discovered first in fish and more recently in mammals. In mammals, the gene is widely expressed and the hormone is, so far, known to be involved in regulating the transport of calcium or phosphate across renal and gut epithelia, and into neuronal cells. Gene expression is also high during development, and in an earlier study we mapped the temporal and spatial pattern of gene expression in the mouse urogenital system. Our data suggested that STC probably acted as a signaling molecule that was produced in mesenchyme cells and targeted to epithelial cell layers in both kidney and testes. Here we have examined STC mRNA and protein distributions between developmental stages E10.5 and E18.5 in the axial and appendicular skeleton. In the axial skeleton, STC was transiently expressed in a rostral-caudal fashion during vertebral development; protein appeared to be made in intervertebral disc mesenchyme cells and targeted to vertebral hypertrophic and prehypertrophic chondrocytes. By stage E18.5, the STC gene was active only in vertebral perichondrocytes. The pattern of expression in the appendicular skeleton was equally striking. Early in development, STC gene expression defined the initial lengths of bone primordia. The gene was expressed in mesenchyme cells at either ends of precartilaginous condensations defining future long bones and the secreted protein was targeted to the chondroblasts. Later on during joint formation, STC was highly expressed in interzone cells that defined all future joints. After cavitation, STC gene expression was greatest in perichondrocytes lining the joints. Underlying resting, proliferative and prehypertrophic chondrocytes appeared to be the targets of STC both during and after cavitation. Therefore, its pattern of expression was indicative of a role in early skeletal patterning and joint formation. Moreover, as occurs during urogenital development, it appeared that STC is made in undifferentiated mesenchyme cells and sequestered by those destined to differentiate.

Animals↗

Engineering gene networks to emulate Drosophila embryonic pattern formation.

Pattern formation is essential in the development of higher eukaryotes. For example, in the Drosophila embryo, maternal morphogen gradients establish gap gene expression domain patterning along the anterior-posterior axis, through linkage with an elaborate gene network. To understand the evolution and behaviour of such systems better, it is important to establish the minimal determinants required for patterning. We have therefore engineered artificial transcription-translation networks that generate simple patterns, crudely analogous to the Drosophila gap gene system. The Drosophila syncytium was modelled using DNA-coated paramagnetic beads fixed by magnets in an artificial chamber, forming a gene expression network. Transient expression domain patterns were generated using various levels of network connectivity. Generally, adding more transcription repression interactions increased the "sharpness" of the pattern while reducing overall expression levels. An accompanying computer model for our system allowed us to search for parameter sets compatible with patterning. While it is clear that the Drosophila embryo is far more complex than our simplified model, several features of interest emerge. For example, the model suggests that simple diffusion may be too rapid for Drosophila-scale patterning, implying that sublocalisation, or "trapping," is required. Second, we find that for pattern formation to occur under the conditions of our in vitro reaction-diffusion system, the activator molecules must propagate faster than the inhibitors. Third, adding controlled protease degradation to the system stabilizes pattern formation over time. We have reconstituted transcriptional pattern formation from purified substances, including phage RNA polymerases, ribonucleotides, and an eukaryotic translation extract. We anticipate that the system described here will be generally applicable to the study of any biological network with a spatial component.

Animals↗

Inhibition of transforming growth factor-beta type II receptor signaling accelerates tooth formation in mouse first branchial arch explants.

Members of the transforming growth factor-beta (TGF-beta) superfamily signal through their cognate receptors to determine cell phenotypes during embryogenesis. Our previous studies on the regulation of first branchial arch morphogenesis have identified critical components of a hierarchy of different TGF-beta isoforms and their possible functions in regulating tooth and cartilage formation during mandibular morphogenesis. Here we tested the hypothesis that TGF-beta type II receptor (TGF-beta IIR) is a critical component in the TGF-beta signaling pathway regulating tooth formation. To establish the precise location of TGF-beta ligand and its cognate receptor, we first performed detailed analyses of the localization of both TGF-beta2 and TGF-beta IIR during initiation and subsequent morphogenesis of developing embryonic mouse tooth organs. A possible autocrine functional role for TGF-beta and its cognate receptor (TGF-beta IIR) was inferred due to the temporal and spatial localization patterns during the early inductive stages of tooth morphogenesis. Second, loss of function of TGF-beta IIR in a mandibular explant culture model resulted in the acceleration of tooth formation to the cap stage while the mandibular explants in the control group only showed bud stage tooth formation. In addition, there was a significant increase in odontogenic epithelial cell proliferation following TGF-beta IIR abrogation. These results demonstrate, for the first time, that abrogation of the TGF-beta IIR stimulates embryonic tooth morphogenesis in culture and reverses the negative regulation of endogenous TGF-beta signaling upon enamel organ epithelial cell proliferation.

Adenoviridae↗

Gene targeting and development of the nervous system.

Gene targeting provides a means of directly assaying the function of specific genes during mouse nervous system development. Generation of targeted mutant mice has provided the first evidence of developmental roles for genes whose function was suggested based on their expression, but for which appropriate assay systems were lacking. In other cases, where gene function was known, targeted mutations have revealed in which cell population, and at what developmental stage, particular genes are first indispensable. The existing targeted mutants suggest that an early mechanism of pattern formation in mammals involves regional control of proliferation or survival of neural precursors, and that later general functions, such as the control of differentiation of precursors, may be performed by different genes in distinct neural lineages. As many genes display complex temporal and spatial patterns of expression, analysis of the full range of functions of such genes will require the generation of a series of alleles, including stage- and tissue-specific mutations.

Animals↗

Expression of homeobox gene Hox 1.1 during mouse embryogenesis.

Many of the genes controlling segmentation and pattern formation in Drosophila contain a conserved 183 bp sequence known as the homeobox. Homeobox sequences have been found in a range of metazoan species, including the vertebrates mouse and man. This striking conservation suggests that homeobox genes may play a fundamental role in developmental processes. If this is the case then it might be expected that vertebrate homeobox genes will be differentially expressed during embryogenesis and that the timing of their expression will coincide with major morphogenetic events. Here the spatial and temporal patterns of expression of murine homeobox genes will be explored, concentrating on the Hox 1.1 gene as an example. Using in situ hybridization to localize RNA transcripts, it has been found that Hox 1.1 is expressed in a region-specific manner during the formation and differentiation of the embryonic anteroposterior axis. Although striking patterns of expression of Hox 1.1 and other homeobox genes are seen in overtly segmented structures of the embryo (i.e. somites, prevertebral elements, neural tube and dorsal spinal ganglia) expression is also seen in tissues with no obvious segmental origin. The results suggest that homeobox genes probably do not play an exclusive role in segmentation in vertebrates, but are consistent with a role in the assignment of positional identity along the axis of the embryo.

Animals↗

Linguistic and conceptual control of visual spatial attention.

A theory of voluntary, top-down control of visual spatial attention is presented that explains how linguistic cues like "above," "below," "left," and "right" are used to direct attention from one object to another. The theory distinguishes between perceptual and conceptual representations of space and views attention as a set of mechanisms that establish correspondences between the representations. Spatial reference frames play an important part in this analysis. The theory interprets reference frames as mechanisms of attention, similar to spatial indices but with more computational power. The theory was tested in 11 experiments that assessed the importance of linguistic distinctions between classes of spatial relations (basic, deictic, and intrinsic) and examined the flexibility with which subjects manipulated spatial reference frames.

Attention↗

Control of chemical pattern formation by a clock-and-wavefront type mechanism.

The segmentation of many animals ranging from insects to mammals involves the sequential formation of stationary stripes of gene expression that are perpendicular to the growth axis of the developing embryo. This process has been accounted for by a variety of theoretical "clock-and-wavefront" type models that involve the arrest of an oscillation (the clock) at a moving boundary (the wavefront). Here, we demonstrate experimentally that progressive arrest of a homogeneous oscillation can control the symmetry as well as the wavelength of spatial structures in a chemical system. We show how a spontaneously formed, labyrinthine pattern can be converted into a pattern composed of ordered, parallel stripes and confirm a previously predicted proportionality between the wavelength and the period of the homogeneous oscillation. Our experiments provide the first experimental demonstration of a general mechanism for the control of pattern formation that has been hypothesized to operate in the context of biological morphogenesis.

Animals↗