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PubMed2006

Arabidopsis TEBICHI, with helicase and DNA polymerase domains, is required for regulated cell division and differentiation in meristems.

In plant meristems, each cell divides and differentiates in a spatially and temporally regulated manner, and continuous organogenesis occurs using cells derived from the meristem. We report the identification of the Arabidopsis thaliana TEBICHI (TEB) gene, which is required for regulated cell division and differentiation in meristems. The teb mutants show morphological defects, such as short roots, serrated leaves, and fasciation, as well as defective patterns of cell division and differentiation in the meristem. The TEB gene encodes a homolog of Drosophila MUS308 and mammalian DNA polymerase theta, which prevent spontaneous or DNA damage-induced production of DNA double strand breaks. As expected from the function of animal homologs, teb mutants show constitutively activated DNA damage responses. Unlike other fasciation mutants with activated DNA damage responses, however, teb mutants do not activate transcriptionally silenced genes. teb shows an accumulation of cells expressing cyclinB1;1:GUS in meristems, suggesting that constitutively activated DNA damage responses in teb lead to a defect in G2/M cell cycle progression. Furthermore, other fasciation mutants, such as fasciata2 and tonsoku/mgoun3/brushy1, also show an accumulation of cells expressing cyclinB1;1:GUS in meristems. These results suggest that cell cycle progression at G2/M is important for the regulation of the pattern of cell division and of differentiation during plant development.

Arabidopsis↗
PubMed1994

Binding by temporal structure in multiple feature domains of an oscillatory neuronal network.

An important step in visual processing is the segregation of objects in a visual scene from one another and from the embedding background. According to current theories of visual neuroscience, the different features of a particular object are represented by cells which are spatially distributed across multiple visual areas in the brain. The segregation of an object therefore requires the unique identification and integration of the pertaining cells which have to be "bound" into one assembly coding for the object in question. Several authors have suggested that such a binding of cells could be achieved by the selective synchronization of temporally structured responses of the neurons activated by features of the same stimulus. This concept has recently gained support by the observation of stimulus-dependent oscillatory activity in the visual system of the cat, pigeon and monkey. Furthermore, experimental evidence has been found for the formation and segregation of synchronously active cell assemblies representing different stimuli in the visual field. In this study, we investigate temporally structured activity in networks with single and multiple feature domains. As a first step, we examine the formation and segregation of cell assemblies by synchronizing and desynchronizing connections within a single feature module. We then demonstrate that distributed assemblies can be appropriately bound in a network comprising three modules selective for stimulus disparity, orientation and colour, respectively. In this context, we address the principal problem of segregating assemblies representing spatially overlapping stimuli in a distributed architecture. Using synchronizing as well as desynchronizing mechanisms, our simulations demonstrate that the binding problem can be solved by temporally correlated responses of cells which are distributed across multiple feature modules.

Animals↗
PubMed1996

A discrete site modulates activation of I domains. Application to integrin alphaMbeta2.

A central characteristic of integrin adhesion receptors is their capacity to become activated, thereby enhancing their affinity for ligands. Here, we report the identification of a discrete site within the I domain of integrin alphaMbeta2, which modulates the adhesive activity of this receptor. Based upon the crystal structure, this region is composed of two short and spatially proximal loops, E162QLKKSKTL and Q190NNPNPRS. Mutations in these loops yield receptors which support spontaneous cell adhesion to fibrinogen, whereas mutation of an adjacent region and wild-type receptors require activation to adhere to this substrate. An activating monoclonal antibody enhanced the adhesive activity of one but not the other loop mutants, suggesting that the activation states of these two mutant receptors were not identical. Given that similar I domains exist in several other integrin alpha subunits and non-integrin proteins, and possibly in all integrin beta subunits, these two loop segments may represent a universal target for controlling integrin activation and the function of other I domain-containing proteins. In support of this hypothesis, several naturally occurring mutations that activate von Willebrand factor map to the same loops of its I(A) domain.

Amino Acid Sequence↗
PubMed1989

Identification and characterization of a gene that is coamplified with dihydrofolate reductase in a methotrexate-resistant CHO cell line.

As part of an effort to characterize the spatial and functional relationships among genetic elements within the amplified dihydrofolate reductase (DHFR) domain in Chinese hamster cells, we have used a variation of the differential hybridization approach to identify cDNA clones whose genes are coamplified with DHFR in the methotrexate-resistant cell line, CHOC 400. Our initial screen was successful in isolating both DHFR and non-DHFR cDNAs. One of the non-DHFR cDNA clones, 2BE2121, hybridizes on Northern (RNA) blots to abundant 1,200- and 1,500-nucleotide (nt) transcripts which differ in the lengths of their 3' untranslated regions. The clone 2BE2121 contains a 789-nt open reading frame but does not appear to be related to any members of the protein or nucleic acid sequence databases. A second larger non-DHFR cDNA, II-19-211, was isolated that is transcribed from the same gene as 2BE2121 but contains only a small carboxyl-terminal portion of the open reading frame. II-19-211 may, therefore, represent either a splicing intermediate or an mRNA transcribed from a cryptic intragenic promoter. Hybridization to cosmids from the DHFR domain shows that 2BE2121 is encoded by a gene approximately 34 kilobases (kb) long. The 5'-most genomic fragment is less than 4 kb from an interamplicon junction. The 3' end of the 2BE2121 gene lies approximately 75 kb downstream from the DHFR gene and approximately 25 kb downstream from the proximal replication initiation site, and the transcriptional polarity is opposite to that of the leading strand of replication. Thus, both the DHFR and 2BE2121 genes are exceptions to the theory that transcription proceeds in the same direction as the leading strand of the replication fork.

Amino Acid Sequence↗
PubMed1998

Receptors determine the cellular localization of a gamma-tubulin complex and thereby the site of microtubule formation.

The yeast microtubule organizing centre (MTOC), known as the spindle pole body (SPB), organizes the nuclear and cytoplasmic microtubules which are functionally and spatially distinct. Microtubule organization requires the yeast gamma-tubulin complex (Tub4p complex) which binds to the nuclear side of the SPB at the N-terminal domain of Spc110p. Here, we describe the identification of the essential SPB component Spc72p whose N-terminal domain interacts with the Tub4p complex on the cytoplasmic side of the SPB. We further report that this Tub4p complex-binding domain of Spc72p is essential and that temperature-sensitive alleles of SPC72 or overexpression of a binding domain-deleted variant of SPC72 (DeltaN-SPC72) impair cytoplasmic microtubule formation. Consequently, polynucleated and anucleated cells accumulated in these cultures. In contrast, overexpression of the entire SPC72 results in more cytoplasmic microtubules compared with wild-type. Finally, exchange of the Tub4p complex-binding domains of Spc110p and Spc72p established that the Spc110p domain, when attached to DeltaN-Spc72p, was functional at the cytoplasmic site of the SPB, while the corresponding domain of Spc72p fused to DeltaN-Spc110p led to a dominant-negative effect. These results suggest that different components of MTOCs act as receptors for gamma-tubulin complexes and that they are essential for the function of MTOCs.

Calmodulin-Binding Proteins↗
PubMed2003

Identification of spatial and temporal cues that regulate postembryonic expression of axon maintenance factors in the C. elegans ventral nerve cord.

Patterns of gene expression are under precise spatial and temporal control. A particularly striking example is represented by several members of the zig gene family, which code for secreted immunoglobulin domain proteins required for maintaining ventral nerve cord organization in Caenorhabditis elegans. These genes are coordinately expressed in a single interneuron in the ventral nerve cord, known as PVT. Their expression is initiated at a precise postembryonic stage, long after PVT has been generated in mid-embryogenesis. We define spatial and temporal cues that are required for the precise regulation of zig gene expression. We find that two LIM homeobox genes, the Lhx3-class gene ceh-14 and the Lmx-class gene lim-6 are coordinately required for zig gene expression in PVT. Temporal control of zig gene expression is conferred by the heterochronic gene lin-14, a nuclear factor previously implicated in developmental timing in various contexts. Loss of the lim-6 and ceh-14 transcription factors and the developmental timer lin-14 cause not only a loss of zig gene expression but also lead to defects in the maintenance of ventral nerve cord architecture. Overriding the normal spatiotemporal control of zig gene expression through expression of one of the zig genes under control of heterologous promoters also causes axon patterning defects in the ventral nerve cord. Our findings illustrate the importance of spatial and temporal control of gene expression in the nervous system and, furthermore, implicate heterochronic genes in postmitotic neural patterning events.

Animals↗
PubMed1991

Regulation and functional involvement of distinct determinants of leucocyte function-associated antigen 1 (LFA-1) in T-cell activation in vitro.

The expression of leucocyte function-associated antigen 1 (LFA-1) was studied by immunofluorescence method on human peripheral blood mononuclear cells (PBMC) stimulated by the phytohaemagglutinin lectin (PHA). Monoclonal antibodies (MoAb) Mas 191c, IOT18 (directed against the beta-chain, 95 kDa, CD18) and IOT16, SPVL7, MHM24 (identificating the alpha-chain, 180 kDa, CD11a) were used, defining the 'CD11a/CD18' antibody panel. By means of cross-linking or competitive experiments, we showed that these antibodies recognized at least four distinct and spatially distant domains on the LFA-1 molecule. Immunofluorescence analysis revealed that the up-regulation of LFA-1 expression was a late event, similar to the expression kinetics of the HLA DR and CD38 molecules, and followed the appearance of CD25 and CD71 molecules. Moreover, it was established that the LFA-1 up-regulation required mRNA and protein synthesis. Functional activity comparison of the different anti LFA-1 MoAb showed that the CD11a MoAb significantly inhibited the proliferation of lymphocytes stimulated by the phytohaemagglutinin to various extents, as the LFA-1 alpha determinant identified. By contrast, the CD18 MoAb did not influence strongly this cell process. We observed only a dim inhibitory effect with the CD18 MoAb recognizing an epitope common or very close to an LFA-1 alpha determinant. These results suggested that the LFA-1 antigen was important, at a molecular level, in the regulation of T-cell activation.

Antigens, Differentiation↗
PubMed1997

Identification of structural elements critical for inter-domain interactions in a group II self-splicing intron.

Thus far, conventional biophysical techniques, such as NMR spectroscopy or X-ray crystallography, allow the determination, at atomic resolution, of only structural domains of large RNA molecules such as group I introns. Determination of their overall spatial organization thus still relies on modeling. This requires that a relatively high number of tertiary interactions are defined in order to get sufficient topological constraints. Here, we report the use of a modification interference assay to identify structural elements involved in interdomain interactions. We used this technique, in a group II intron, to identify the elements involved in the interactions between domain V and the rest of the molecule. Domain V contains many of the active site components of these ribozymes. In addition to a previously identified 11 nucleotide motif involved in the binding of the domain V terminal GAAA tetraloop, a small number of elements were shown to be essential for domain V binding. In particular, we show that domain III is specifically required for the interaction with sequences encompassing the conserved 2 nucleotide bulge of domain V.

Introns↗
PubMed1995

Molecular characterization and spatial distribution of SAP97, a novel presynaptic protein homologous to SAP90 and the Drosophila discs-large tumor suppressor protein.

Synapses are highly specialized sites of cell-cell contact involved in signal transfer. The molecular mechanisms modulating the assembly and stability of synapses are unknown. We previously reported the identification of a 90 kDa synapse-associated protein, SAP90, that is localized at the presynaptic termini of inhibitory GABAergic synapses. SAP90 is a mosaic protein composed of three 90 amino acid residue repeats, an SH3 domain and a region homologous to guanylate kinases. SAP90 shares domain specific homology with a family of proteins involved in the assembly and possibly stability of sites of cell contact. These include the product of the lethal(1) discs-large-1 (dlgA) tumor suppressor gene and the zonula occludens proteins ZO-1, ZO-2. The further characterization of cDNA clones encoding components of synaptic junctions has lead to the identification of a 97 kDa protein, called SAP97, that exhibits a strong overall sequence similarity to SAP90. The present study was undertaken to determine the spatial distribution of SAP97, and to reveal further clues to the possible roles of these proteins in synapses. Light and immunoelectron microscopic analysis of the rat hippocampal formation revealed that SAP97 is localized in the presynaptic nerve termini of excitatory synapses. In other brain regions, SAP97 is found in and along bundles of unmyelinated axons. SAP97 is not restricted to the CNS, but is also present at the basal lateral membrane between a variety of epithelial cells. In cultured T84 cells, it is restricted to the cytoplasmic surface of the plasma membranes between adjacent cells, but not at the edges of cells lacking cell-cell contact suggesting a role for SAP97 in cell adhesion. These data suggest that members of the SAP90/SAP97 subfamily may be involved in the site specific assembly, stability or functions of membrane specialization at sites of cell-cell contact.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Cytochemistry of the functional domains of the nucleus in normal and in pathologic conditions.

By means of ultrastructural cytochemistry significant advances have been made in understanding the functional roles of many nuclear domains. This review gives schematic information about the main nuclear domains involved in replication, transcription, processing and transport of the transcripts in normal and in pathologic conditions. Particular attention is paid to a functional domain that appears to be involved in signal transduction. Data are reported on the intranuclear specific localization of key elements of the polyphosphoinositide signal transduction system in different cell types including human osteosarcoma cell lines. Compared with the compartmentalization of the cytoplasm, the nucleus has long been considered as relatively unstructured. On the other hand, fundamental nuclear functions, such as DNA replication and RNA transcription, can be molecularly characterized also in cell-free systems, suggesting that supramolecular organization is not so strictly required as for other cell functions occurring within intact cytoplasmic organelles. Nevertheless, a stringent organization is required for packing about 200 cm of DNA in the about 30 micron 3 of the nucleus. In the absence of membrane-delimited organelles, the nuclear organization is based on functional compartments, or domains, whose spatial localization involves the nuclear matrix, which shares many properties with the cytoskeleton. The nuclear domains are defined as structural compartments, not necessarily stable but dynamically variable, which perform specific metabolic functions through the partitioning of molecular complexes. Their identification has been made possible in the last few years by the development of specific nuclear probes for confocal and electron microscope immunocytochemistry. Therefore, the complex network of structures and enzymatic functions that make up the nucleus is in several cases yielding to molecular analysis, but a large part remains unknown (Strouboulis and Wolffe, 1996; Laemmli and Tjian, 1996). Rapid advances in understanding the functional role of the nuclear domains have been made recently: in particular, of the nuclear envelope, of the nucleolus, and of RNA splicing. In other cases, e.g. the precise localization of the nuclear domains involved in signal transduction, much remains to be clarified (Forbes and Johnson, 1997). It is conceivable that in the near future unexpected new nuclear domains will come to light and new nuclear functions may emerge, especially in field of post-transcriptional processing and transport of RNAs, and in the relationships between the nucleo-skeleton and enzymic fixed sites involved in replication, transcription and signal transduction. The aim of this review is to provide information about the morphological characteristics, the associated functions and the molecular composition of the main nuclear domains found to date. To simplify the exposition, the main data on each nuclear domain are reported in Tables, together with the principal references on the subject. Figures refer to original findings on some aspects of nuclear domain organization.

Cell Nucleus↗
PubMed1991

GTPase domains of ras p21 oncogene protein and elongation factor Tu: analysis of three-dimensional structures, sequence families, and functional sites.

GTPase domains are functional and structural units employed as molecular switches in a variety of important cellular functions, such as growth control, protein biosynthesis, and membrane traffic. Amino acid sequences of more than 100 members of different subfamilies are known, but crystal structures of only mammalian ras p21 and bacterial elongation factor Tu have been determined. After optimal superposition of these remarkably similar structures, careful multiple sequence alignment, and calculation of residue-residue interactions, we analyzed the two subfamilies in terms of structural conservation, sequence conservation, and residue contact strength. There are three main results. (i) A structure-based alignment of p21 and elongation factor Tu. (ii) The definition of a common conserved structural core that may be useful as the basis of model building by homology of the three-dimensional structure of any GTPase domain. (iii) Identification of sequence regions, other than the effector loop and the nucleotide binding site, that may be involved in the functional cycle: they are loop L4, known to change conformation after GTP hydrolysis; helix alpha 2, especially Arg-73 and Met-67 in ras p21; loops L8 and L10, including ras p21 Arg-123, Lys-147, and Leu-120; and residues located spatially near the N and C termini. These regions are candidate sites for interaction either with the GTP/GDP exchange factor, with a GTPase-affected function, or with a molecule delivered to a destination site with the aid of the GTPase domain.

Amino Acid Sequence↗
PubMed2005

Probing phosphoinositide functions in signaling and membrane trafficking.

The inositol phospholipids (PIs) comprise a family of eight species with different combinations of phosphate groups arranged around the inositol ring. PIs are among the most versatile signaling molecules known, with key roles in receptor-mediated signal transduction, actin remodeling and membrane trafficking. Recent studies have identified effector proteins and specific lipid-binding domains through which PIs signal. These lipid-binding domains can be used as probes to further our understanding of the spatial and temporal control of individual PI species. New layers of complexity revealed by the use of such probes include the occurrence of PIs at intracellular locations, the identification of phosphatidylinositol signaling hotspots and the presence of non-membrane pools of PIs in cell nuclei.

Cell Membrane↗
PubMed1999

Identification of a photoreceptor cell-specific nuclear receptor.

Nuclear receptors comprise a large and expanding family of transcription factors involved in diverse aspects of animal physiology and development, the functions of which can be modulated in a spatial and temporal manner by access to small lipophilic ligands and/or the specificity of their own localized expression. Here we report the identification of a human nuclear receptor that reveals a unique proximal box (CNGCSG) in the DNA-binding domain. The conservation of this feature in its nematode counterpart suggests the requirement for this type of P box in the genetic cascades mediated by nuclear receptors in a wide variety of animal species. The expression of this receptor, PNR (photoreceptor-specific nuclear receptor), appears strongly restricted in the retina, exclusively in photoreceptor cells. In human cell lines, PNR expression was observed in Y79 retinoblastoma along with other photoreceptor marker genes such as CRX. Among vertebrate receptors, PNR shares structural kinship with an orphan receptor TLX, and despite distinct differences in the DNA binding domain, PNR is able to recognize a subset of TLX target sequences in vitro. Analyses of the human PNR gene revealed its chromosomal position as 15q24, a site that has recently been reported as a susceptible region for retinal degeneration. These data support a role for PNR in the regulation of signalling pathways intrinsic to the photoreceptor cell function.

Amino Acid Sequence↗
PubMed1991

Expression of a retinoic acid response element-hsplacZ transgene defines specific domains of transcriptional activity during mouse embryogenesis.

Treatment with retinoic acid (RA) is known to produce complex teratogenic effects in vertebrates, and its presence in the developing embryo as an endogenous substance has led to the suggestion that RA might be a natural morphogenetic agent. Although our understanding of the molecular mechanism of RA action has improved considerably with the identification of nuclear receptors for RA (RARs) and RA-responsive genes, the exact relationship between the proposed morphogenetic activity of RA and its teratogenic effects remains to be characterized. Here, we show that a RA response element (RARE) present in the RAR beta gene can direct specific spatial and temporal expression of an hsplacZ transgene during mouse embryogenesis. In the early embryo, the transgene is expressed in a specific anterior-posterior domain that is completely obliterated by treatment of pregnant mice with teratogenic doses of RA. The expression of the transgene becomes more restricted as organogenesis progresses and mimics closely the reported expression of the RAR beta gene. These results suggest that, in vivo, some of the morphogenetic effects of RA could be mediated through localized transcriptional activity controlled by the various RARs. The specific pattern of expression of the RAREhsplacZ transgene does not correlate with the proposed sites of action of RA as defined by its teratogenic effects but does support a role for RA in early anterior-posterior patterning along the body axis.

Animals↗
PubMed2003

Alexia and related reading disorders.

Peripheral dyslexias are the result of impairment to processes that convert letters on the page into an abstract orthographic representation. Many aspects of these disorders are difficult to understand in depth. Invariably, there is evidence that some type of word-level perception occurs rapidly in many patients with LBL reading or neglect dyslexia, yet apparently contradictory evidence indicates that part of the word has been misperceived or that the letters must be analyzed laboriously for conscious identification to occur. Current theories attempt to synthesize these different aspects of the patients' performance, but their development is at an early stage. Questions remain also about the domain specificity of the perceptual impairment in LBL reading and about the nature of spatial attention and spatial frames in neglect dyslexia and other forms of attentional disorder. Current understanding of central dyslexias has perhaps advanced further. Well-developed computational models exist of these dyslexias, as do plausible experimental techniques for revealing the activity of semantic and non-semantic routes in normal readers. Nevertheless, the difficult issue of domain specificity arises again with respect to some of the mechanisms invoked, and in this regard, central and peripheral dyslexias continue to pose the same challenge.

Attention↗
PubMed2005

Multidimensional measures of person knowledge and spatial associative learning: can these be applied to the differentiation of Alzheimer's disease from frontotemporal and vascular dementia?

Patients with early stage Alzheimer's disease (AD) show deficits in person knowledge and spatial associative memory. The current investigation examined the ability of impairment in these domains to differentiate AD from other overlapping conditions. In experiment 1, 14 AD patients, 21 vascular dementia (VaD) patients, 11 frontal variant frontotemporal dementia (fvFTD) patients and 41 controls were administered a graded faces test. VaD patients demonstrated a level of impairment comparable to the AD group on both the naming and person identification elements of the task. A mild naming deficit was revealed in the fvFTD group. In experiment 2, 22 AD patients, 23 patients with mild cognitive impairment (MCI), 11 fvFTD patients, 13 semantic dementia (SD) patients, and 23 elderly controls were administered the face-place test, a newly developed task that combines naming of famous faces, item recognition and spatial location. The naming component of the face-place test clearly differentiated SD patients from all dementia groups. All patient groups, except those with fvFTD, showed substantial deficits in the item recognition and spatial components. Consistency analyses indicated a fairly robust association between the two episodic components (item recognition and placing), but not between semantic and episodic elements of the FPT. Person knowledge deficits are, therefore, not specific to AD and the employment of face stimuli may influence the performance of SD patients on tasks of episodic memory.

Aged↗
PubMed1997

Domain motions in dihydrofolate reductase: a molecular dynamics study.

Molecular dynamics simulations have been carried out on the enzyme dihydrofolate reductase from Lactobacillus casei complexed with methotrexate, NADPH and 264 crystallographic water molecules. Analysis of correlations in atomic fluctuations reveal the presence of highly correlated motion (correlation coefficient > 0.6) in the region between residues 30 to 35 and 85 to 90 leading to the identification of two domains, an "adenosine-binding domain" and a "large domain", which rotate by 3 to 4 degrees with respect to each other. The strongest correlation (> 0.6) within the large domain involves a coupling between the motions of the "teen-loop", and the spatially contiguous loops linking beta 6-beta 7 and beta 7-beta 8. Moreover, there is a significant correlation (approximately 0.5) between the adenosine fragment of NADPH and the pteridine and p-aminobenzoyl fragments of methotrexate, which are separated by approximately 17 A, and is lost on removal of "rigid-body" motion from the original trajectory. This provides support for the idea that the relative motion of the two domains is a means by which the occupation of the binding site for the adenosine end of the coenzyme can affect methotrexate binding and vice versa. Quasiharmonic vibrational analysis of the trajectory reveals that the overall dynamics of the system are governed by domain motions whose contributions are dominant at low frequencies. In addition, different low-frequency modes are responsible for separately coupling the adenosine-binding site and parts of methotrexate.

Binding Sites↗
PubMed1999

Identification of the stef gene that encodes a novel guanine nucleotide exchange factor specific for Rac1.

The Rho family GTPases are involved in a variety of cellular events by changing the organization of actin cytoskeletal networks in response to extracellular signals. However, it is not clearly known how their activities are spatially and temporally regulated. Here we report the identification of a novel guanine nucleotide exchange factor for Rac1, STEF, which is related in overall amino acid sequence and modular structure to mouse Tiam1 and Drosophila SIF proteins. STEF protein contains two pleckstrin homology domains, a PDZ domain and a Dbl homology domain. The in vitro assay showed that STEF protein specifically enhanced the dissociation of GDP from Rac1 but not that from either RhoA or Cdc42. Expression of a truncated STEF protein in culture cells induced membrane ruffling with altered actin localization, which implies that this protein also activates Rac1 in vivo. The stef transcript was observed in restricted parts of mice, including cartilaginous tissues and the cortical plate of the central nervous system during embryogenesis. These findings suggested that STEF protein participates in the control of cellular events in several developing tissues, possibly changing the actin cytoskeletal network by activating Rac1.

Amino Acid Sequence↗