Biological solutions to transport network design

Transport networks are vital components of multicellular organisms, distributing nutrients and removing waste products. Animal and plant transport systems are branching trees whose architecture is linked to universal scaling laws in these organisms. In contrast, many fungi form reticulated mycelia via the branching and fusion of thread-like hyphae that continuously adapt to the environment. Fungal networks have evolved to explore and exploit a patchy environment, rather than ramify through a three-dimensional organism. However, there has been no explicit analysis of the network structures formed, their dynamic behaviour nor how either impact on their ecological function. Using the woodland saprotroph Phanerochaete velutina, we show that fungal networks can display both high transport capacity and robustness to damage. These properties are enhanced as the network grows, while the relative cost of building the network decreases. Thus, mycelia achieve the seemingly competing goals of efficient transport and robustness, with decreasing relative investment, by selective reinforcement and recycling of transport pathways. Fungal networks demonstrate that indeterminate, decentralized systems can yield highly adaptive networks. Understanding how these relatively simple organisms have found effective transport networks through a process of natural selection may inform the design of man-made networks.     

Heart development in fibronectin-null mice is governed by a genetic modifier on chromosome four

Absence of the fibronectin (FN) gene leads to early embryonic lethality in both 129S4 and C57BL/6J strains due to severe cardiovascular defects. However, heart development is arrested at different stages in these embryos depending on the genetic background. In the majority of 129S4 FN-null embryos, heart progenitors remain at their anterior bilateral positions and fail to fuse at the midline to form a heart tube. However, on the C57BL/6J genetic background, cardiac development progresses further and results in a centrally positioned and looped heart. To find factor(s) involved in embryonic heart formation and governing the extent of heart development in FN-null embryos in 129S4 and C57BL/6J strains, we performed genetic mapping and haplotype analyses. These analyses lead to identification of a significant linkage to a 1-Mbp interval on chromosome four. Microarray analysis and sequencing identified 21 genes in this region, including five that are differentially expressed between the strains, as potential modifiers. Since none of these genes was previously known to play a role in heart development, one or more of them is likely to be a novel modifier affecting cardiac development. Identification of the modifier would significantly enhance our understanding of the molecular underpinning of heart development and disease.     

Quantifying heritable variation in fitness-related traits of wild,farmed and hybrid Atlantic salmon families in a wild river environment

Farmed fish are typically genetically different from wild conspecifics. Escapees from fish farms may contribute one-way gene flow from farm to wild gene pools, which can depress population productivity, dilute local adaptations and disrupt coadapted gene complexes. Here, we reanalyse data from two experiments (McGinnity et al., 1997, 2003) where performance of Atlantic salmon (Salmo salar) progeny originating from experimental crosses between farm and wild parents (in three different cohorts) were measured in a natural stream under common garden conditions. Previous published analyses focussed on group-level differences but did not account for pedigree structure, as we do here using modern mixed-effect models. Offspring with one or two farm parents exhibited poorer survival in their first and second year of life compared with those with two wild parents and these group-level inferences were robust to excluding outlier families. Variation in performance among farm, hybrid and wild families was generally similar in magnitude. Farm offspring were generally larger at all life stages examined than wild offspring, but the differences were moderate (5–20%) and similar in magnitude in the wild versus hatchery environments. Quantitative genetic analyses conducted using a Bayesian framework revealed moderate heritability in juvenile fork length and mass and positive genetic correlations (>0.85) between these morphological traits. Our study confirms (using more rigorous statistical techniques) previous studies showing that offspring of wild fish invariably have higher fitness and contributes fresh insights into family-level variation in performance of farm, wild and hybrid Atlantic salmon families in the wild. It also adds to a small, but growing, number of studies that estimate key evolutionary parameters in wild salmonid populations. Such information is vital in modelling the impacts of introgression by escaped farm salmon.     

Platelet adhesion and degranulation induce pro-survival and pro-angiogenic signalling in ovarian cancer cells

Thrombosis is common in ovarian cancer. However, the interaction of platelets with ovarian cancer cells has not been critically examined. To address this, we investigated platelet interactions in a range of ovarian cancer cell lines with different metastatic potentials [HIO-80, 59M, SK-OV-3, A2780, A2780cis]. Platelets adhered to ovarian cancer cells with the most significant adhesion to the 59M cell line. Ovarian cancer cells induced platelet activation [P-selectin expression] in a dose dependent manner, with the most significant activation seen in response to the 59M cell line. The platelet antagonists [cangrelor, MRS2179, and apyrase] inhibited 59M cell induced activation suggesting a P2Y12 and P2Y1 receptor mediated mechanism of platelet activation dependent on the release of ADP by 59M cells. A2780 and 59M cells potentiated PAR-1, PAR-4, and TxA2 receptor mediated platelet activation, but had no effect on ADP, epinephrine, or collagen induced activation. Analysis of gene expression changes in ovarian cancer cells following treatment with washed platelets or platelet releasate showed a subtle but valid upregulation of anti-apoptotic, anti-autophagy pro-angiogenic, pro-cell cycle and metabolic genes. Thus, ovarian cancer cells with different metastatic potential adhere and activate platelets differentially while both platelets and platelet releasate mediate pro-survival and pro-angiogenic signals in ovarian cancer cells.     

Self-renewing Pten-/- TP53-/- protospheres produce metastatic adenocarcinoma cell lines with multipotent progenitor activity

Prostate cancers of luminal adenocarcinoma histology display a range of clinical behaviors. Although most prostate cancers are slow-growing and indolent, a proportion is aggressive, developing metastasis and resistance to androgen deprivation treatment. One hypothesis is that a portion of aggressive cancers initiate from stem-like, androgen-independent tumor-propagating cells. Here we demonstrate the in vitro creation of a mouse cell line, selected for growth as self-renewing stem/progenitor cells, which manifests many in vivo properties of aggressive prostate cancer. Normal mouse prostate epithelium containing floxed Pten and TP53 alleles was subjected to CRE-mediated deletion in vitro followed by serial propagation as protospheres. A polyclonal cell line was established from dissociated protospheres and subsequently a clonal daughter line was derived. Both lines demonstrate a mature luminal phenotype in vitro. The established lines contain a stable minor population of progenitor cells with protosphere-forming ability and multi-lineage differentiation capacity. Both lines formed orthotopic adenocarcinoma tumors with metastatic potential to lung. Intracardiac inoculation resulted in brain and lung metastasis, while intra-tibial injection induced osteoblastic bone formation, recapitulating the bone metastatic phenotype of human prostate cancer. The cells showed androgen receptor dependent growth in vitro. Importantly, in vivo, the deprivation of androgens from established orthotopic tumors resulted in tumor regression and eventually castration-resistant growth. These data suggest that transformed prostate progenitor cells preferentially differentiate toward luminal cells and recapitulate many characteristics of the human disease.     

Beta1 integrins regulate mammary gland proliferation and maintain the integrity of mammary alveoli

Integrin-extracellular matrix interactions play important roles in the coordinated integration of external and internal cues that are essential for proper development. To study the role of beta1 integrin in the mammary gland, Itgbeta1(flox/flox) mice were crossed with WAPiCre transgenic mice, which led to specific ablation of beta1 integrin in luminal alveolar epithelial cells. In the beta1 integrin mutant mammary gland, individual alveoli were disorganized resulting from alterations in cell-basement membrane associations. Activity of focal adhesion kinase (FAK) was also decreased in mutant mammary glands. Luminal cell proliferation was strongly inhibited in beta1 integrin mutant glands, which correlated with a specific increase of p21 Cip1 expression. In a p21 Cip1 null background, there was a partial rescue of BrdU incorporation, providing in vivo evidence linking p21 Cip1 to the proliferative defect observed in beta1 integrin mutant glands. A connection between p21 Cip1 and beta1 integrin as well as FAK was also established in primary mammary cells. These results point to the essential role of beta1 integrin signaling in mammary epithelial cell proliferation.