Short-range cell interactions and cell survival in the Drosophila wing

During development of multicellular organisms, cells are often eliminated by apoptosis if they fail to receive appropriate signals from their surroundings. Here, we report on short-range cell interactions that support cell survival in the Drosophila wing imaginal disc. We present evidence showing that cells incorrectly specified for their position undergo apoptosis because they fail to express specific proteins that are found on surrounding cells, including the LRR transmembrane proteins Capricious and Tartan. Interestingly, only the extracellular domains of Capricious and Tartan are required, suggesting that a bidirectional process of cell communication is involved in triggering apoptosis. We also present evidence showing that activation of the Notch signal transduction pathway is involved in triggering apoptosis of cells misspecified for their dorsal-ventral position.     

A Highlights from MBoC Selection: Mitotic regulation of fungal cell-to-cell connectivity through septal pores involves the NIMA kinase

Intercellular bridges are a conserved feature of multicellular organisms. In multicellular fungi, cells are connected directly via intercellular bridges called septal pores. Using Aspergillus nidulans, we demonstrate for the first time that septal pores are regulated to be opened during interphase but closed during mitosis. Septal pore–associated proteins display dynamic cell cycle–regulated locations at mature septa. Of importance, the mitotic NIMA kinase locates to forming septa and surprisingly then remains at septa throughout interphase. However, during mitosis, when NIMA transiently locates to nuclei to promote mitosis, its levels at septa drop. A model is proposed in which NIMA helps keep septal pores open during interphase and then closed when it is removed from them during mitosis. In support of this hypothesis, NIMA inactivation is shown to promote interphase septal pore closing. Because NIMA triggers nuclear pore complex opening during mitosis, our findings suggest that common cell cycle regulatory mechanisms might control septal pores and nuclear pores such that they are opened and closed out of phase to each other during cell cycle progression. The study provides insights into how and why cytoplasmically connected Aspergillus cells maintain mitotic autonomy.     

Cyclic-AMP binding to the cell surface during development of Dictyostelium discoideum

Abstract. Cell aggregation in Dictyostelium discoideum is a chemotactic process mediated by cyclic adenosine monophosphate (CAMP), which is detected by cell surface receptors. The cAMP signal is degraded by cAMP phosphodiesterase. The possibility that cAMP signals are also used for cell communication in the multicellular stages was studied by determining whether the cAMP receptors, which are essential for signal transduction, continue to function in these stages. During slug migration, the number of binding sites per cell decreases to about 15% of the maximum level acquired during aggregation. At the onset of fruiting body formation, a three- to Four-Fold increase in cAMP binding activity occurs. This increase coincides with an increase in cAMP phosphodiesterase. Both phenomena suggest that cell-cell communication mediated by cAMP is used during culmination. During both slug migration and early culmination, the prestalk cells exhibit about twice as much binding activity as the prespore cells.     

On a Model of Pattern Regeneration Based on Cell Memory

We present here a new model of the cellular dynamics that enable regeneration of complex biological morphologies. Biological cell structures are considered as an ensemble of mathematical points on the plane. Each cell produces a signal which propagates in space and is received by other cells. The total signal received by each cell forms a signal distribution defined on the cell structure. This distribution characterizes the geometry of the cell structure. If a part of this structure is removed, the remaining cells have two signals. They keep the value of the signal which they had before the amputation (memory), and they receive a new signal produced after the amputation. Regeneration of the cell structure is stimulated by the difference between the old and the new signals. It is stopped when the two signals coincide. The algorithm of regeneration contains certain rules which are essential for its functioning, being the first quantitative model of cellular memory that implements regeneration of complex patterns to a specific target morphology. Correct regeneration depends on the form and the size of the cell structure, as well as on some parameters of regeneration.     

Intercellular communication and carcinogenesis

Two types of intercellular communication (humoral and cell contact-mediated) are involved in control of cellular function in multicellular organisms, both of them mediated by membrane-embedded proteins. Involvement of aberrant humoral communication in carcinogenesis has been well documented and genes coding for some growth factors and their receptors have been classified as oncogenes. More recently, cell contact-mediated communication has been found to have an important role in carcinogenesis, and some genes coding for proteins involved in this type of communication appear to form a family of tumor-suppressor genes. Both homologous (among normal or (pre-)cancerous cells) as well as heterologous (between normal and (pre)cancerous cells) communications appear to play important roles in cell growth control. Gap junctional intercellular communication (GJIC) is the only means by which multicellular organisms can exchange low molecular weight signals directly from within one cell to the interior of neighboring cells. GJIC is altered by many tumor-promoting agents and in many human and rodent tumors. We have recently shown that liver tumor-promoting agents inhibit GJIC in the rat liver in vivo. Molecular mechanisms which could lead to aberrant GJIC include: (1) mutation of connexin genes; (2) reduced and/or aberrant expression of connexin mRNA; (3) aberrant localization of connexin proteins, i.e., intracytoplasmic rather than in the cytoplasmic membrane; and (4) modulation of connexin functions by other proteins, such as those involved in extracellular matrix and cell adhesion. Whilst mutations of the cx 32 gene appear to be rare in tumors, cx 37 gene mutations have been reported in a mouse lung tumor cell line. Our results suggest that aberrant connexin localization is rather common in cancer cells and that possible molecular mechanisms include aberrant phosphorylation of connexin proteins and lack of cell adhesion molecules. Studies on transfection of connexin genes into tumor cells suggest that certain connexin genes (e.g., cx 26, cx 43 and cx 32) act as tumor-suppressor genes.     

The second cell membrane: the basal lamina and the tissue cell theory of metazoa.

We suggest that the basal lamina is essentially a second plasma or cell membrane appearing at the next higher level of biological organization; that together with associated cell monolayers it creates a tissue level membrane which is used to form multicellular cells and that collections of these provide the essential structure of metazoa. Thus when the histological structure of multicellular organisms is viewed in a topologically simplified form such organisms appear to be sets of multicellular cells (m-cells) formed by a unit tissue membrane built around the basal lamina. Not only are m-cells in this way structurally isomorphous (homeomorphic) to unit or classical biological cells (u-cells) but the two cellular levels are also functionally isomorphous. This suggests a “General Principle of Hierarchical Isomorphism or Iteration”, i.e. that multicellular evolution recapitulates unicellular evolution. This principle of structural and functional isomorphic mappability of unicellular onto multicellular organisms then governs the organization of matter all the way from molecules to man. Just as cytoplasm precipitates the bimolecular plasma membrane to form u-cells for the purpose of achieving reaction sequestration, in turn, these u-cells precipitate a common basal lamina to form m-cells, the histologist's acini, to produce sequestered “tissue plasms”. Thus, the “generalized acinus” with its basal laminar complex seem to constitute a second level (multicellular) cell and cell membrane, respectively.Four operators, ultimately under genetic control, can generate both u and m-cells from planar configurations of their respective unit membranes therewith providing the essential structure of all cells, tissues, organs and organisms. These are the ply, permeability vector, topological and stratificational operators. They are collected into a set of “organ formulae”. Both the plasma membrane and the basal lamina act as covering membranes and, again, as membranes for subcells so that a complete multicellular organism is a tetrahierarchical cell in which the molecule is the element of the first two cellular domains and the cell is the element of the last two. The analysis identifies a new transport organ group which together with the classical endocrine and exocrine groups comprises nearly the whole of the soft tissue organs. In a major reduction, all these organs are continuously (topologically) transformable into each and into hollow spheres, cells or acini thus greatly simplifying the histology of metazoa. Given this emphasis on cellularization it would seem that life, i.e. the autonomous chemoservo, results from the cooperation of cellularization and replication operations on the catalyzation process. Through cellularization, the lipid bilayer and basal laminar membranes provide the essential catalytic reaction sequestration demanded by chemical reaction theory while through complementary base pairing the DNA double helix provides the essential memory which stores the patterns of the variations of the sequestered reactions.     

Chloroplast Import Signals: The Length Requirement for Translocation In Vitro and In Vivo

Protein translocation of cytosolically synthesized proteins requires signals for both targeting of precursor proteins to the surface of the respective compartment and their transfer across its membrane. In contrast to signals for peroxisomal and endoplasmic reticulum translocation, the signals for mitochondrial and chloroplast transport are less well defined with respect to length and amino acid requirements. To study the properties of signals required for translocation into chloroplasts in vitro and in vivo, we used fusion proteins composed of transit peptides and the Ig-like module of the muscle protein titin as passenger. We observed that about 60 amino acids—longer than the transit peptide length of many experimentally confirmed chloroplast proteins—are required for efficient translocation. However, within native chloroplast precursor proteins with transit peptides shorter than 60 amino acids, extension appears to be present as they are efficiently imported into organelles. In addition, the interaction of an unfolded polypeptide stretch of 60 or more amino acids with receptors at the chloroplast surface results in the unidirectionality of protein translocation into chloroplasts even in the presence of a competing C-terminal peroxisomal targeting signal. These findings prove the existing ideas that initial targeting is defined by the N-terminal signal and that the C-terminal signal is sensed only subsequently.     

Persistent cell motion in the absence of external signals: a search strategy for eukaryotic cells

Background

Eukaryotic cells are large enough to detect signals and then orient to them by differentiating the signal strength across the length and breadth of the cell. Amoebae, fibroblasts, neutrophils and growth cones all behave in this way. Little is known however about cell motion and searching behavior in the absence of a signal. Is individual cell motion best characterized as a random walk? Do individual cells have a search strategy when they are beyond the range of the signal they would otherwise move toward? Here we ask if single, isolated, Dictyostelium and Polysphondylium amoebae bias their motion in the absence of external cues.

Methodology

We placed single well-isolated Dictyostelium and Polysphondylium cells on a nutrient-free agar surface and followed them at 10 sec intervals for ∼10 hr, then analyzed their motion with respect to velocity, turning angle, persistence length, and persistence time, comparing the results to the expectation for a variety of different types of random motion.

Conclusions

We find that amoeboid behavior is well described by a special kind of random motion: Amoebae show a long persistence time (∼10 min) beyond which they start to lose their direction; they move forward in a zig-zag manner; and they make turns every 1–2 min on average. They bias their motion by remembering the last turn and turning away from it. Interpreting the motion as consisting of runs and turns, the duration of a run and the amplitude of a turn are both found to be exponentially distributed. We show that this behavior greatly improves their chances of finding a target relative to performing a random walk. We believe that other eukaryotic cells may employ a strategy similar to Dictyostelium when seeking conditions or signal sources not yet within range of their detection system.