Molecular mechanism of size control in development and human diseases

How multicellular organisms control their size is a fundamental question that fascinated generations of biologists. In the past 10 years, tremendous progress has been made toward our understanding of the molecular mechanism underlying size control. Original studies from Drosophila showed that in addition to extrinsic nutritional and hormonal cues, intrinsic mechanisms also play important roles in the control of organ size during development. Several novel signaling pathways such as insulin and Hippo-LATS signaling pathways have been identified that control organ size by regulating cell size and/or cell number through modulation of cell growth, cell division, and cell death. Later studies using mammalian cell and mouse models also demonstrated that the signaling pathways identified in flies are also conserved in mammals. Significantly, recent studies showed that dysregulation of size control plays important roles in the development of many human diseases such as cancer, diabetes, and hypertrophy.     

A matter of size: developmental control of organ size in plants

The intrinsic size of plant organs is determined by developmental signals, yet the molecular and genetic mechanisms that control organ size are largely unknown. Ongoing functional analysis of Arabidopsis genes is defining important regulators involved in these mechanisms. Key features of this control are the coordinated activation of growth and cell division by growth regulators and the maintenance of meristematic competence by the ANT gene, which acts as an organ-size checkpoint. Alterations of genome size by polyploidization and endoreduplication can reset this checkpoint by ploidy-dependent, epigenetically regulated differential gene expression. In addition, the regulation of polarized growth and phytohormone signaling also affect final organ size. These findings reveal unique aspects of plant organ-size control that are distinct from animal organ-size control.     

Cell cycle,cell size and mitochondrial activity of hybridoma cells during batch cultivation

Cell cycle, cell size and rhodamine 123 fluorescence in cell populations of two batch cultures were analysed and quantified with a fluorescence-activated cell sorter (FACS). Two cultures derived from either exponential or stationary phase innocula were investigated in order to demonstrate the dependency of the subsequent cell growth on innoculum condition. The results demonstrated that the level of activity of cells in the innoculum culture could have a significant effect on cellular activity during the initial phase of the inoculated culture, as it advances through its growth cycle. Positive correlation was found between the cell size and mitochondrial activity (as measured by rhodamine 123 uptake) with S and G₂ fractions as the cell progressed through the cell cycle. The enumeration of the fractions of cell cycle phases has helped in prediction of the changes in cell numbers following perturbation of the culture condition.     

Cell size as a tool to predict the production of recombinant protein by the insect-cell baculovirus expression system

The increase of Sf9 cell diameter after infection with a recombinant baculovirus encoding VP8 protein of rotavirus can be used to predict culture productivity. A direct proportional correlation between the increase in cell size and VP8 concentration was obtained when manipulating selected medium components. Only yeast extract increased (38%) VP8 concentration, while fetal bovine serum increased (55%) the maximum cell concentration. An inexpensive and simplified culture media can thus be designed without detriment to protein yields.     

Xylem ingestion by aphids – a strategy for maintaining water balance

A new waveform, pattern G, detected during recording of electrical penetration graphs (EPG's) from aphids was strongly correlated with uptake from radioactively labelled artificial diets. During pattern G, maxillary stylet tips were located within xylem conductive elements and it was concluded that pattern G is representative of ingestion of xylem sap. Dehydrated aphids showed a higher incidence and greater duration of xylem uptake, suggesting that its occurrence is related to the water balance of the insect.

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Résumé Une nouvelle onde, de type G, décelée pendant l'enregistrement des électropénétrogrammes (EPG's) des pucerons est nettement associée à la prise d'aliments marqués radioactivement. Pendant l'onde G, les extrémités des stylets maxillaires sont situées dans les éléments conducteurs du xylème et l'on en conclu que l'onde G représente l'ingestion du contenu du xylème. Les pucerons déshydratés présentent une plus grande fréquence et une durée plus longue d'absorption de xylème, ce qui suggère qu'elle est liée à l'équilibre hydrique de l'insecte.

     

MRE11–RAD50–NBS1 is a critical regulator of FANCD2 stability and function during DNA double‐strand break repair

Monoubiquitination of the Fanconi anaemia protein FANCD2 is a key event leading to repair of interstrand cross‐links. It was reported earlier that FANCD2 co‐localizes with NBS1. However, the functional connection between FANCD2 and MRE11 is poorly understood. In this study, we show that inhibition of MRE11, NBS1 or RAD50 leads to a destabilization of FANCD2. FANCD2 accumulated from mid‐S to G2 phase within sites containing single‐stranded DNA (ssDNA) intermediates, or at sites of DNA damage, such as those created by restriction endonucleases and laser irradiation. Purified FANCD2, a ring‐like particle by electron microscopy, preferentially bound ssDNA over various DNA substrates. Inhibition of MRE11 nuclease activity by Mirin decreased the number of FANCD2 foci formed in vivo. We propose that FANCD2 binds to ssDNA arising from MRE11‐processed DNA double‐strand breaks. Our data establish MRN as a crucial regulator of FANCD2 stability and function in the DNA damage response.     

Gene duplications and the time thereafter – examples from plant secondary metabolism

Gene duplications are regarded as one of the central mechanisms for the origin of new genes. Recent studies in plant secondary metabolism have provided several examples of genes that originated by duplication with successive diversification. In this review, the mechanisms of gene duplication are explained and several models discussed that suggest the way that gene duplicates develop into genes with new functions. Signatures of gene duplication and diversification processes are discussed using the biosynthesis of benzoxazinones and of pyrrolizidine alkaloids as examples.     

Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity

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Pre‐conditions for eliminating mitochondrial dysfunction and maintaining liver function after hepatic ischaemia reperfusion

The liver, the largest organ with multiple synthesis and secretion functions in mammals, consists of hepatocytes and Kupffer, stem, endothelial, stellate and other parenchymal cells. Because of early and extensive contact with the external environment, hepatic ischaemia reperfusion (IR) may result in mitochondrial dysfunction, autophagy and apoptosis of cells and tissues under various pathological conditions. Because the liver requires a high oxygen supply to maintain normal detoxification and synthesis functions, it is extremely susceptible to ischaemia and subsequent reperfusion with blood. Consequently, hepatic IR leads to acute or chronic liver failure and significantly increases the total rate of morbidity and mortality through multiple regulatory mechanisms. An increasing number of studies indicate that mitochondrial structure and function are impaired after hepatic IR, but that the health of liver tissues or liver grafts can be effectively rescued by attenuation of mitochondrial dysfunction. In this review, we mainly focus on the subsequent therapeutic interventions related to the conservation of mitochondrial function involved in mitigating hepatic IR injury and the potential mechanisms of protection. Because mitochondria are abundant in liver tissue, clarification of the regulatory mechanisms between mitochondrial dysfunction and hepatic IR should shed light on clinical therapies for alleviating hepatic IR‐induced injury.     

Revising traditional theory on the link between plant body size and fitness under competition: evidence from old‐field vegetation

The selection consequences of competition in plants have been traditionally interpreted based on a “size‐advantage” hypothesis – that is, under intense crowding/competition from neighbors, natural selection generally favors capacity for a relatively large plant body size. However, this conflicts with abundant data, showing that resident species body size distributions are usually strongly right‐skewed at virtually all scales within vegetation. Using surveys within sample plots and a neighbor‐removal experiment, we tested: (1) whether resident species that have a larger maximum potential body size (MAX) generally have more successful local individual recruitment, and thus greater local abundance/density (as predicted by the traditional size‐advantage hypothesis); and (2) whether there is a general between‐species trade‐off relationship between MAX and capacity to produce offspring when body size is severely suppressed by crowding/competition – that is, whether resident species with a larger MAX generally also need to reach a larger minimum reproductive threshold size (MIN) before they can reproduce at all. The results showed that MIN had a positive relationship with MAX across resident species, and local density – as well as local density of just reproductive individuals – was generally greater for species with smaller MIN (and hence smaller MAX). In addition, the cleared neighborhoods of larger target species (which had relatively large MIN) generally had – in the following growing season – a lower ratio of conspecific recruitment within these neighborhoods relative to recruitment of other (i.e., smaller) species (which had generally smaller MIN). These data are consistent with an alternative hypothesis based on a ‘reproductive‐economy‐advantage’ – that is, superior fitness under competition in plants generally requires not larger potential body size, but rather superior capacity to recruit offspring that are in turn capable of producing grand‐offspring – and hence transmitting genes to future generations – despite intense and persistent (cross‐generational) crowding/competition from near neighbors. Selection for the latter is expected to favor relatively small minimum reproductive threshold size and hence – as a tradeoff – relatively small (not large) potential body size.     

Exotic ladybirds for biological control of herbivorous insects – a review

Since the late 19th century, exotic ladybirds (Coleoptera: Coccinellidae) have been used extensively for suppressing herbivorous insects of economic importance. In recent decades, the introduction of non‐native biological control (BC) agents has been greatly limited due to the awareness of the potential non‐target effects of introductions. Nonetheless, recent episodes of biological invasions of economically important pests have raised the need to carefully consider whether the expected benefits of pest control go beyond the possible environmental risks of introduction. To better understand the factors that contributed to successful BC programs, here we review the literature behind classical and augmentative BC using exotic ladybirds. Additionally, by means of case studies, we discuss the BC efficacy of selected exotic species, e.g., Coccinella septempunctata L., Harmonia axyridis (Pallas), and Hippodamia variegata (Goeze), and their position within the communities of predators in the introduced areas of USA, Canada, and Chile. In Europe, much of the research on exotic ladybirds has been conducted on the undesired impact of H. axyridis. Therefore, we summarize the risk assessment data for this species and review the field research investigating the ecological impact on European aphidophagous predators. According to the BIOCAT database of classical BC programs, 212 ladybird species belonging to 68 genera have been released in about 130 years of BC activity, with 14.6% of introductions having resulted in partial, substantial, or complete control of the target pest. However, because post‐release evaluation of establishment and BC success has not always been conducted, this rate could underestimate the successful cases. Among other factors, ladybird establishment and pest suppression mostly depend on (1) intrinsic factors, i.e., high voracity, synchronized predator‐prey life cycle, and high dispersal ability, and (2) extrinsic factors, i.e., adaptability to the new environment and landscape composition. This review contributes to improved understanding of ladybirds as exotic BC agents.     

Heterozygosity–fitness correlations in a wild mammal population: accounting for parental and environmental effects

HFCs (heterozygosity–fitness correlations) measure the direct relationship between an individual's genetic diversity and fitness. The effects of parental heterozygosity and the environment on HFCs are currently under‐researched. We investigated these in a high‐density U.K. population of European badgers (Meles meles), using a multimodel capture–mark–recapture framework and 35 microsatellite loci. We detected interannual variation in first‐year, but not adult, survival probability. Adult females had higher annual survival probabilities than adult males. Cubs with more heterozygous fathers had higher first‐year survival, but only in wetter summers; there was no relationship with individual or maternal heterozygosity. Moist soil conditions enhance badger food supply (earthworms), improving survival. In dryer years, higher indiscriminate mortality rates appear to mask differential heterozygosity‐related survival effects. This paternal interaction was significant in the most supported model; however, the model‐averaged estimate had a relative importance of 0.50 and overlapped zero slightly. First‐year survival probabilities were not correlated with the inbreeding coefficient (f); however, small sample sizes limited the power to detect inbreeding depression. Correlations between individual heterozygosity and inbreeding were weak, in line with published meta‐analyses showing that HFCs tend to be weak. We found support for general rather than local heterozygosity effects on first‐year survival probability, and g2 indicated that our markers had power to detect inbreeding. We emphasize the importance of assessing how environmental stressors can influence the magnitude and direction of HFCs and of considering how parental genetic diversity can affect fitness‐related traits, which could play an important role in the evolution of mate choice.     

Loss of growth homeostasis by genetic decoupling of cell division from biomass growth: implication for size control mechanisms

Growing cells adjust their division time with biomass accumulation to maintain growth homeostasis. Size control mechanisms, such as the size checkpoint, provide an inherent coupling of growth and division by gating certain cell cycle transitions based on cell size. We describe genetic manipulations that decouple cell division from cell size, leading to the loss of growth homeostasis, with cells becoming progressively smaller or progressively larger until arresting. This was achieved by modulating glucose influx independently of external glucose. Division rate followed glucose influx, while volume growth was largely defined by external glucose. Therefore, the coordination of size and division observed in wild‐type cells reflects tuning of two parallel processes, which is only refined by an inherent feedback‐dependent coupling. We present a class of size control models explaining the observed breakdowns of growth homeostasis.     

Cell size,genome size,and maximum growth rate are near‐independent dimensions of ecological variation across bacteria and archaea

Among bacteria and archaea, maximum relative growth rate, cell diameter, and genome size are widely regarded as important influences on ecological strategy. Via the most extensive data compilation so far for these traits across all clades and habitats, we ask whether they are correlated and if so how. Overall, we found little correlation among them, indicating they should be considered as independent dimensions of ecological variation. Nor was correlation evident within particular habitat types. A weak nonlinearity (6% of variance) was found whereby high maximum growth rates (temperature‐adjusted) tended to occur in the midrange of cell diameters. Species identified in the literature as oligotrophs or copiotrophs were clearly separated on the dimension of maximum growth rate, but not on the dimensions of genome size or cell diameter.     

Local plant density,pollination and trait–fitness relationships in a perennial herb

Both differences in local plant density and phenotypic traits may affect pollination and plant reproduction, but little is known about how density affects trait–fitness relationships via changes in pollinator activity. In this study we examined how plant density and traits interact to determine pollinator behaviour and female reproductive success in the self‐incompatible, perennial herb Phyteuma spicatum. Specifically, we hypothesised that limited pollination service in more isolated plants would lead to increased selection for traits that attract pollinators. We conducted pollinator observations and assessed trait–fitness relationships in a natural population, whose individuals were surrounded by a variable number of inflorescences. Both local plant density and plant phenotypic traits affected pollinator foraging behaviour. At low densities, pollinator visitation rates were low, but increased with increasing inflorescence size, while this relationship disappeared at high densities, where visitation rates were higher. Plant fitness, in terms of seed production per plant and per capsule, was related to both floral display size and flowering time. Seed production increased with increasing inflorescence size and was highest at peak flowering. However, trait–fitness relationships were not density‐dependent, and differences in seed production did not appear to be related to differences in pollination. The reasons for this remain unclear, and additional studies are needed to fully understand and explain the observed patterns.