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26.  Long-range regulatory interactions at the 4q25 atrial fibrillation risk locus involve PITX2c and ENPEP 
BMC Biology  2015;13:26.
Background
Recent genome-wide association studies have uncovered genomic loci that underlie an increased risk for atrial fibrillation, the major cardiac arrhythmia in humans. The most significant locus is located in a gene desert at 4q25, approximately 170 kilobases upstream of PITX2, which codes for a transcription factor involved in embryonic left-right asymmetry and cardiac development. However, how this genomic region functionally and structurally relates to PITX2 and atrial fibrillation is unknown.
Results
To characterise its function, we tested genomic fragments from 4q25 for transcriptional activity in a mouse atrial cardiomyocyte cell line and in transgenic mouse embryos, identifying a non-tissue-specific potentiator regulatory element. Chromosome conformation capture revealed that this region physically interacts with the promoter of the cardiac specific isoform of Pitx2. Surprisingly, this regulatory region also interacts with the promoter of the next neighbouring gene, Enpep, which we show to be expressed in regions of the developing mouse heart essential for cardiac electrical activity.
Conclusions
Our data suggest that de-regulation of both PITX2 and ENPEP could contribute to an increased risk of atrial fibrillation in carriers of disease-associated variants, and show the challenges that we face in the functional analysis of genome-wide disease associations.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0138-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0138-0
PMCID: PMC4416339  PMID: 25888893
Atrial fibrillation; Chromosome conformation; ENPEP; PITX2; Regulatory element
27.  Molecular basis of sugar recognition by collectin-K1 and the effects of mutations associated with 3MC syndrome 
BMC Biology  2015;13:27.
Background
Collectin-K1 (CL-K1, or CL-11) is a multifunctional Ca2+-dependent lectin with roles in innate immunity, apoptosis and embryogenesis. It binds to carbohydrates on pathogens to activate the lectin pathway of complement and together with its associated serine protease MASP-3 serves as a guidance cue for neural crest development. High serum levels are associated with disseminated intravascular coagulation, where spontaneous clotting can lead to multiple organ failure. Autosomal mutations in the CL-K1 or MASP-3 genes cause a developmental disorder called 3MC (Carnevale, Mingarelli, Malpuech and Michels) syndrome, characterised by facial, genital, renal and limb abnormalities. One of these mutations (Gly204Ser in the CL-K1 gene) is associated with undetectable levels of protein in the serum of affected individuals.
Results
In this study, we show that CL-K1 primarily targets a subset of high-mannose oligosaccharides present on both self- and non-self structures, and provide the structural basis for its ligand specificity. We also demonstrate that three disease-associated mutations prevent secretion of CL-K1 from mammalian cells, accounting for the protein deficiency observed in patients. Interestingly, none of the mutations prevent folding or oligomerization of recombinant fragments containing the mutations in vitro. Instead, they prevent Ca2+ binding by the carbohydrate-recognition domains of CL-K1. We propose that failure to bind Ca2+ during biosynthesis leads to structural defects that prevent secretion of CL-K1, thus providing a molecular explanation of the genetic disorder.
Conclusions
We have established the sugar specificity of CL-K1 and demonstrated that it targets high-mannose oligosaccharides on self- and non-self structures via an extended binding site which recognises the terminal two mannose residues of the carbohydrate ligand. We have also shown that mutations associated with a rare developmental disorder called 3MC syndrome prevent the secretion of CL-K1, probably as a result of structural defects caused by disruption of Ca2+ binding during biosynthesis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0136-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0136-2
PMCID: PMC4431178  PMID: 25912189
Complement activation; structural biology; C-type lectin; 3MC syndrome
28.  Gene-specific selective sweeps in bacteria and archaea caused by negative frequency-dependent selection 
BMC Biology  2015;13:20.
Background
Fixation of beneficial genes in bacteria and archaea (collectively, prokaryotes) is often believed to erase pre-existing genomic diversity through the hitchhiking effect, a phenomenon known as genome-wide selective sweep. Recent studies, however, indicate that beneficial genes spread through a prokaryotic population via recombination without causing genome-wide selective sweeps. These gene-specific selective sweeps seem to be at odds with the existing estimates of recombination rates in prokaryotes, which appear far too low to explain such phenomena.
Results
We use mathematical modeling to investigate potential solutions to this apparent paradox. Most microbes in nature evolve in heterogeneous, dynamic communities, in which ecological interactions can substantially impact evolution. Here, we focus on the effect of negative frequency-dependent selection (NFDS) such as caused by viral predation (kill-the-winner dynamics). The NFDS maintains multiple genotypes within a population, so that a gene beneficial to every individual would have to spread via recombination, hence a gene-specific selective sweep. However, gene loci affected by NFDS often are located in variable regions of microbial genomes that contain genes involved in the mobility of selfish genetic elements, such as integrases or transposases. Thus, the NFDS-affected loci are likely to experience elevated rates of recombination compared with the other loci. Consequently, these loci might be effectively unlinked from the rest of the genome, so that NFDS would be unable to prevent genome-wide selective sweeps. To address this problem, we analyzed population genetic models of selective sweeps in prokaryotes under NFDS. The results indicate that NFDS can cause gene-specific selective sweeps despite the effect of locally elevated recombination rates, provided NFDS affects more than one locus and the basal rate of recombination is sufficiently low. Although these conditions might seem to contradict the intuition that gene-specific selective sweeps require high recombination rates, they actually decrease the effective rate of recombination at loci affected by NFDS relative to the per-locus basal level, so that NFDS can cause gene-specific selective sweeps.
Conclusion
Because many free-living prokaryotes are likely to evolve under NFDS caused by ubiquitous viruses, gene-specific selective sweeps driven by NFDS are expected to be a major, general phenomenon in prokaryotic populations.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0131-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0131-7
PMCID: PMC4410459  PMID: 25928466
29.  snoRNAs are a novel class of biologically relevant Myc targets 
BMC Biology  2015;13:25.
Background
Myc proteins are essential regulators of animal growth during normal development, and their deregulation is one of the main driving factors of human malignancies. They function as transcription factors that (in vertebrates) control many growth- and proliferation-associated genes, and in some contexts contribute to global gene regulation.
Results
We combine chromatin immunoprecipitation-sequencing (ChIPseq) and RNAseq approaches in Drosophila tissue culture cells to identify a core set of less than 500 Myc target genes, whose salient function resides in the control of ribosome biogenesis. Among these genes we find the non-coding snoRNA genes as a large novel class of Myc targets. All assayed snoRNAs are affected by Myc, and many of them are subject to direct transcriptional activation by Myc, both in Drosophila and in vertebrates. The loss of snoRNAs impairs growth during normal development, whereas their overexpression increases tumor mass in a model for neuronal tumors.
Conclusions
This work shows that Myc acts as a master regulator of snoRNP biogenesis. In addition, in combination with recent observations of snoRNA involvement in human cancer, it raises the possibility that Myc’s transforming effects are partially mediated by this class of non-coding transcripts.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0132-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0132-6
PMCID: PMC4430873  PMID: 25888729
Myc; Transcription; snoRNA; Ribosome; Growth; Drosophila
30.  Distinct adhesion-independent functions of β-catenin control stage-specific sensory neurogenesis and proliferation 
BMC Biology  2015;13:24.
Background
β-catenin plays a central role in multiple developmental processes. However, it has been difficult to study its pleiotropic effects, because of the dual capacity of β-catenin to coordinate cadherin-dependent cell adhesion and to act as a component of Wnt signal transduction. To distinguish between the divergent functions of β-catenin during peripheral nervous system development, we made use of a mutant allele of β-catenin that can mediate adhesion but not Wnt-induced TCF transcriptional activation. This allele was combined with various conditional inactivation approaches.
Results
We show that of all peripheral nervous system structures, only sensory dorsal root ganglia require β-catenin for proper formation and growth. Surprisingly, however, dorsal root ganglia development is independent of cadherin-mediated cell adhesion. Rather, both progenitor cell proliferation and fate specification are controlled by β-catenin signaling. These can be divided into temporally sequential processes, each of which depends on a different function of β-catenin.
Conclusions
While early stage proliferation and specific Neurog2- and Krox20-dependent waves of neuronal subtype specification involve activation of TCF transcription, late stage progenitor proliferation and Neurog1-marked sensory neurogenesis are regulated by a function of β-catenin independent of TCF activation and adhesion. Thus, switching modes of β-catenin function are associated with consecutive cell fate specification and stage-specific progenitor proliferation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0134-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0134-4
PMCID: PMC4416270  PMID: 25885041
Sensory neurogenesis; Cell fate decisions; Cellular proliferation; Canonical Wnt signaling; Signaling versus adhesion function of β-catenin
31.  Hox genes pattern the anterior-posterior axis of the juvenile but not the larva in a maximally indirect developing invertebrate, Micrura alaskensis (Nemertea) 
BMC Biology  2015;13:23.
Background
The pilidium larva is a novel body plan that arose within a single clade in the phylum Nemertea - the Pilidiophora. While the sister clade of the Pilidiophora and the basal nemerteans develop directly, pilidiophorans have a long-lived planktotrophic larva with a body plan distinctly different from that of the juvenile. Uniquely, the pilidiophoran juvenile develops inside the larva from several discrete rudiments. The orientation of the juvenile with respect to the larval body varies within the Pilidiophora, which suggests that the larval and juvenile anteroposterior (AP) axes are patterned differently. In order to gain insight into the evolutionary origins of the pilidium larva and the mechanisms underlying this implied axial uncoupling, we examined the expression of the Hox genes during development of the pilidiophoran Micrura alaskensis.
Results
We identified sequences of nine Hox genes and the ParaHox gene caudal through a combination of transcriptome analysis and molecular cloning, and determined their expression pattern during development using in situ hybridization in whole-mounted larvae. We found that Hox genes are first expressed long after the pilidium is fully formed and functional. The Hox genes are expressed in apparently overlapping domains along the AP axis of the developing juvenile in a subset of the rudiments that give rise to the juvenile trunk. Hox genes are not expressed in the larval body at any stage of development.
Conclusions
While the Hox genes pattern the juvenile pilidiophoran, the pilidial body, which appears to be an evolutionary novelty, must be patterned by some mechanism other than the Hox genes. Although the pilidiophoran juvenile develops from separate rudiments with no obvious relationship to the embryonic formation of the larva, the Hox genes appear to exhibit canonical expression along the juvenile AP axis. This suggests that the Hox patterning system can maintain conserved function even when widely decoupled from early polarity established in the egg.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0133-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0133-5
PMCID: PMC4426647  PMID: 25888821
Biphasic life cycle; Hox; Indirect development; Larval evolution; Nemertea; Pilidium
32.  Mitophagy and the mitochondrial unfolded protein response in neurodegeneration and bacterial infection 
BMC Biology  2015;13:22.
Mitochondria are highly dynamic and structurally complex organelles that provide multiple essential metabolic functions. Mitochondrial dysfunction is associated with neurodegenerative conditions such as Parkinson’s disease, as well as bacterial infection. Here, we explore the roles of mitochondrial autophagy (mitophagy) and the mitochondrial unfolded protein response (UPRmt) in the response to mitochondrial dysfunction, focusing in particular on recent evidence on the role of mitochondrial import efficiency in the regulation of these stress pathways and how they may interact to protect the mitochondrial pool while initiating an innate immune response to protect against bacterial pathogens.
doi:10.1186/s12915-015-0129-1
PMCID: PMC4384303  PMID: 25857750
33.  The recently identified modifier of murine metastable epialleles, Rearranged L-Myc Fusion, is involved in maintaining epigenetic marks at CpG island shores and enhancers 
BMC Biology  2015;13:21.
Background
We recently identified a novel protein, Rearranged L-myc fusion (Rlf), that is required for DNA hypomethylation and transcriptional activity at two specific regions of the genome known to be sensitive to epigenetic gene silencing. To identify other loci affected by the absence of Rlf, we have now analysed 12 whole genome bisulphite sequencing datasets across three different embryonic tissues/stages from mice wild-type or null for Rlf.
Results
Here we show that the absence of Rlf results in an increase in DNA methylation at thousands of elements involved in transcriptional regulation and many of the changes occur at enhancers and CpG island shores. ChIP-seq for H3K4me1, a mark generally found at regulatory elements, revealed associated changes at many of the regions that are differentially methylated in the Rlf mutants. RNA-seq showed that the numerous effects of the absence of Rlf on the epigenome are associated with relatively subtle effects on the mRNA population. In vitro studies suggest that Rlf’s zinc fingers have the capacity to bind DNA and that the protein interacts with other known epigenetic modifiers.
Conclusion
This study provides the first evidence that the epigenetic modifier Rlf is involved in the maintenance of DNA methylation at enhancers and CGI shores across the genome.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0128-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0128-2
PMCID: PMC4381397  PMID: 25857663
Rearranged L-Myc Fusion; Rlf; DNA methylation; Enhancers; Bisulphite
34.  Population genomic evidence for adaptive differentiation in Baltic Sea three-spined sticklebacks 
BMC Biology  2015;13:19.
Background
The degree of genetic differentiation among populations experiencing high levels of gene flow is expected to be low for neutral genomic sites, but substantial divergence can occur in sites subject to directional selection. Studies of highly mobile marine fish populations provide an opportunity to investigate this kind of heterogeneous genomic differentiation, but most studies to this effect have focused on a relatively low number of genetic markers and/or few populations. Hence, the patterns and extent of genomic divergence in high-gene-flow marine fish populations remain poorly understood.
Results
We here investigated genome-wide patterns of genetic variability and differentiation in ten marine populations of three-spined stickleback (Gasterosteus aculeatus) distributed across a steep salinity and temperature gradient in the Baltic Sea, by utilizing >30,000 single nucleotide polymorphisms obtained with a pooled RAD-seq approach. We found that genetic diversity and differentiation varied widely across the genome, and identified numerous fairly narrow genomic regions exhibiting signatures of both divergent and balancing selection. Evidence was uncovered for substantial genetic differentiation associated with both salinity and temperature gradients, and many candidate genes associated with local adaptation in the Baltic Sea were identified.
Conclusions
The patterns of genetic diversity and differentiation, as well as candidate genes associated with adaptation, in Baltic Sea sticklebacks were similar to those observed in earlier comparisons between marine and freshwater populations, suggesting that similar processes may be driving adaptation to brackish and freshwater environments. Taken together, our results provide strong evidence for heterogenic genomic divergence driven by local adaptation in the face of gene flow along an environmental gradient in the post-glacially formed Baltic Sea.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0130-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0130-8
PMCID: PMC4410466  PMID: 25857931
Gasterosteus aculeatus; RAD-sequencing; SNP, population differentiation; local adaptation; Baltic Sea
35.  Distribution and impact of yeast thermal tolerance permissive for mammalian infection 
BMC Biology  2015;13:18.
Background
From the viewpoint of fungal virulence in mammals, thermal tolerance can be defined as the ability to grow in the 35°C to 40°C range, which is essential for inhabiting these hosts.
Results
We used archival information in a fungal collection to analyze the relationship between thermal tolerance and genetic background for over 4,289 yeast strains belonging to 1,054 species. Fungal genetic relationships were inferred from hierarchical trees based on pairwise alignments using the rRNA internal transcribed spacer and large subunit rDNA (LSU) sequences. In addition, we searched for correlations between thermal tolerance and other archival information including antifungal susceptibility, carbon sources, and fermentative capacity. Thermal tolerance for growth at mammalian temperatures was not monophyletic, with thermally tolerant species being interspersed among families that include closely related species that are not thermal tolerant. Thermal tolerance and resistance to antifungal drugs were not correlated, suggesting that these two properties evolved independently. Nevertheless, the ability to grow at higher temperatures did correlate with origin from lower geographic latitudes, capacity for fermentation and assimilation of certain carbon sources.
Conclusions
Thermal tolerance was significantly more common among ascomycetous than basidiomycetous yeasts, suggesting an explanation for the preponderance of ascomycetous yeasts among human pathogenic fungi. Analysis of strain maximum tolerable temperature as a function of collection time suggested that basidiomycetous yeasts are rapidly adapting to global warming. The analysis identified genera with a high prevalence of the thermal-tolerant species that could serve as sources of emerging pathogenic fungi.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0127-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0127-3
PMCID: PMC4381509  PMID: 25762372
Disease; Fungi; Mammal; Taxonomy; Temperature
36.  Testing ecological theories with sequence similarity networks: marine ciliates exhibit similar geographic dispersal patterns as multicellular organisms 
BMC Biology  2015;13:16.
Background
High-throughput sequencing technologies are lifting major limitations to molecular-based ecological studies of eukaryotic microbial diversity, but analyses of the resulting millions of short sequences remain a major bottleneck for these approaches. Here, we introduce the analytical and statistical framework of sequence similarity networks, increasingly used in evolutionary studies and graph theory, into the field of ecology to analyze novel pyrosequenced V4 small subunit rDNA (SSU-rDNA) sequence data sets in the context of previous studies, including SSU-rDNA Sanger sequence data from cultured ciliates and from previous environmental diversity inventories.
Results
Our broadly applicable protocol quantified the progress in the description of genetic diversity of ciliates by environmental SSU-rDNA surveys, detected a fundamental historical bias in the tendency to recover already known groups in these surveys, and revealed substantial amounts of hidden microbial diversity. Moreover, network measures demonstrated that ciliates are not globally dispersed, but are structured by habitat and geographical location at intermediate geographical scale, as observed for bacteria, plants, and animals.
Conclusions
Currently available ‘universal’ primers used for local in-depth sequencing surveys provide little hope to exhaust the significantly higher ciliate (and most likely microbial) diversity than previously thought. Network analyses such as presented in this study offer a promising way to guide the design of novel primers and to further explore this vast and structured microbial diversity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0125-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0125-5
PMCID: PMC4381497  PMID: 25762112
Biogeography; Microbial diversity; High-throughput sequencing; Environmental rDNA sequencing; Protist
37.  Dawn- and dusk-phased circadian transcription rhythms coordinate anabolic and catabolic functions in Neurospora 
BMC Biology  2015;13:17.
Background
Circadian clocks control rhythmic expression of a large number of genes in coordination with the 24 hour day-night cycle. The mechanisms generating circadian rhythms, their amplitude and circadian phase are dependent on a transcriptional network of immense complexity. Moreover, the contribution of post-transcriptional mechanisms in generating rhythms in RNA abundance is not known.
Results
Here, we analyzed the clock-controlled transcriptome of Neurospora crassa together with temporal profiles of elongating RNA polymerase II. Our data indicate that transcription contributes to the rhythmic expression of the vast majority of clock-controlled genes (ccgs) in Neurospora. The ccgs accumulate in two main clusters with peak transcription and expression levels either at dawn or dusk. Dawn-phased genes are predominantly involved in catabolic and dusk-phased genes in anabolic processes, indicating a clock-controlled temporal separation of the physiology of Neurospora. Genes whose expression is strongly dependent on the core circadian activator WCC fall mainly into the dawn-phased cluster while rhythmic genes regulated by the glucose-dependent repressor CSP1 fall predominantly into the dusk-phased cluster. Surprisingly, the number of rhythmic transcripts increases about twofold in the absence of CSP1, indicating that rhythmic expression of many genes is attenuated by the activity of CSP1.
Conclusions
The data indicate that the vast majority of transcript rhythms in Neurospora are generated by dawn and dusk specific transcription. Our observations suggest a substantial plasticity of the circadian transcriptome with respect to the number of rhythmic genes as well as amplitude and phase of the expression rhythms and emphasize a major role of the circadian clock in the temporal organization of metabolism and physiology.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0126-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0126-4
PMCID: PMC4381671  PMID: 25762222
Circadian; WCC; CSP1; Transcriptome; RNA-seq; ChIP-seq; RNAPII; Metabolism
38.  Distinct genetic architecture underlies the emergence of sleep loss and prey-seeking behavior in the Mexican cavefish 
BMC Biology  2015;13:15.
Background
Sleep is characterized by extended periods of quiescence and reduced responsiveness to sensory stimuli. Animals ranging from insects to mammals adapt to environments with limited food by suppressing sleep and enhancing their response to food cues, yet little is known about the genetic and evolutionary relationship between these processes. The blind Mexican cavefish, Astyanax mexicanus is a powerful model for elucidating the genetic mechanisms underlying behavioral evolution. A. mexicanus comprises an extant ancestral-type surface dwelling morph and at least five independently evolved cave populations. Evolutionary convergence on sleep loss and vibration attraction behavior, which is involved in prey seeking, have been documented in cavefish raising the possibility that enhanced sensory responsiveness underlies changes in sleep.
Results
We established a system to study sleep and vibration attraction behavior in adult A. mexicanus and used high coverage quantitative trait loci (QTL) mapping to investigate the functional and evolutionary relationship between these traits. Analysis of surface-cave F2 hybrid fish and an outbred cave population indicates that independent genetic factors underlie changes in sleep/locomotor activity and vibration attraction behavior. High-coverage QTL mapping with genotyping-by-sequencing technology identify two novel QTL intervals that associate with locomotor activity and include the narcolepsy-associated tp53 regulating kinase. These QTLs represent the first genomic localization of locomotor activity in cavefish and are distinct from two QTLs previously identified as associating with vibration attraction behavior.
Conclusions
Taken together, these results localize genomic regions underlying sleep/locomotor and sensory changes in cavefish populations and provide evidence that sleep loss evolved independently from enhanced sensory responsiveness.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0119-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0119-3
PMCID: PMC4364459  PMID: 25761998
Sleep; Sensory perception; Astyanax mexicanus; Cavefish; Foraging
39.  Control of organ size: development, regeneration, and the role of theory in biology 
BMC Biology  2015;13:14.
How organs grow to be the right size for the animal is one of the central mysteries of biology. In a paper in BMC Biology, Khammash et al. propose a mechanism for escaping from the deficiencies of feedback control of growth as a mechanism.
See research article: http://dx.doi.org/10.1186/s12915-015-0122-8
doi:10.1186/s12915-015-0123-7
PMCID: PMC4334576  PMID: 25706761
40.  The development and maintenance of the mononuclear phagocyte system of the chick is controlled by signals from the macrophage colony-stimulating factor receptor 
BMC Biology  2015;13:12.
Background
Macrophages have many functions in development and homeostasis as well as innate immunity. Recent studies in mammals suggest that cells arising in the yolk sac give rise to self-renewing macrophage populations that persist in adult tissues. Macrophage proliferation and differentiation is controlled by macrophage colony-stimulating factor (CSF1) and interleukin 34 (IL34), both agonists of the CSF1 receptor (CSF1R). In the current manuscript we describe the origin, function and regulation of macrophages, and the role of CSF1R signaling during embryonic development, using the chick as a model.
Results
Based upon RNA-sequencing comparison to bone marrow-derived macrophages grown in CSF1, we show that embryonic macrophages contribute around 2% of the total embryo RNA in day 7 chick embryos, and have similar gene expression profiles to bone marrow-derived macrophages. To explore the origins of embryonic and adult macrophages, we injected Hamburger-Hamilton stage 16 to 17 chick embryos with either yolk sac-derived blood cells, or bone marrow cells from EGFP+ donors. In both cases, the transferred cells gave rise to large numbers of EGFP+ tissue macrophages in the embryo. In the case of the yolk sac, these cells were not retained in hatched birds. Conversely, bone marrow EGFP+ cells gave rise to tissue macrophages in all organs of adult birds, and regenerated CSF1-responsive marrow macrophage progenitors. Surprisingly, they did not contribute to any other hematopoietic lineage. To explore the role of CSF1 further, we injected embryonic or hatchling CSF1R-reporter transgenic birds with a novel chicken CSF1-Fc conjugate. In both cases, the treatment produced a large increase in macrophage numbers in all tissues examined. There were no apparent adverse effects of chicken CSF1-Fc on embryonic or post-hatch development, but there was an unexpected increase in bone density in the treated hatchlings.
Conclusions
The data indicate that the yolk sac is not the major source of macrophages in adult birds, and that there is a macrophage-restricted, self-renewing progenitor cell in bone marrow. CSF1R is demonstrated to be limiting for macrophage development during development in ovo and post-hatch. The chicken provides a novel and tractable model to study the development of the mononuclear phagocyte system and CSF1R signaling.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0121-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0121-9
PMCID: PMC4369834  PMID: 25857347
Chicken; CSF1; Hematopoiesis; Macrophage; Transgenic
41.  Cell lineage branching as a strategy for proliferative control 
BMC Biology  2015;13:13.
Background
How tissue and organ sizes are specified is one of the great unsolved mysteries in biology. Experiments and mathematical modeling implicate feedback control of cell lineage progression, but a broad understanding of what lineage feedback accomplishes is lacking.
Results
By exploring the possible effects of various biologically relevant disturbances on the dynamic and steady state behaviors of stem cell lineages, we find that the simplest and most frequently studied form of lineage feedback - which we term renewal control - suffers from several serious drawbacks. These reflect fundamental performance limits dictated by universal conservation-type laws, and are independent of parameter choice. Here we show that introducing lineage branches can circumvent all such limitations, permitting effective attenuation of a wide range of perturbations. The type of feedback that achieves such performance - which we term fate control - involves promotion of lineage branching at the expense of both renewal and (primary) differentiation. We discuss the evidence that feedback of just this type occurs in vivo, and plays a role in tissue growth control.
Conclusions
Regulated lineage branching is an effective strategy for dealing with disturbances in stem cell systems. The existence of this strategy provides a dynamics-based justification for feedback control of cell fate in vivo.
See commentary article: http://dx.doi.org/10.1186/s12915-015-0123-7.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0122-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0122-8
PMCID: PMC4378012  PMID: 25857410
Cell fate; Control theory; Differentiation; Feedback control; Growth control; Homeostasis; Proliferative dynamics; Mathematical modeling; Robustness; Self-renewal; Stem cells; Tradeoffs
42.  A stable JAZ protein from peach mediates the transition from outcrossing to self-pollination 
BMC Biology  2015;13:11.
Background
Variations in floral display represent one of the core features associated with the transition from allogamy to autogamy in angiosperms. The promotion of autogamy under stress conditions suggests the potential involvement of a signaling pathway with a dual role in both flower development and stress response. The jasmonic acid (JA) pathway is a plausible candidate to play such a role because of its involvement in many plant responses to environmental and developmental cues. In the present study, we used peach (Prunus persica L.) varieties with showy and non-showy flowers to investigate the role of JA (and JA signaling suppressors) in floral display.
Results
Our results show that PpJAZ1, a component of the JA signaling pathway in peach, regulates petal expansion during anthesis and promotes self-pollination. PpJAZ1 transcript levels were higher in petals of the non-showy flowers than those of showy flowers at anthesis. Moreover, the ectopic expression of PpJAZ1 in tobacco (Nicotiana tabacum L.) converted the showy, chasmogamous tobacco flowers into non-showy, cleistogamous flowers. Stability of PpJAZ1 was confirmed in vivo using PpJAZ1-GFP chimeric protein. PpJAZ1 inhibited JA-dependent processes in roots and leaves of transgenic plants, including induction of JA-response genes to mechanical wounding. However, the inhibitory effect of PpJAZ1 on JA-dependent fertility functions was weaker, indicating that PpJAZ1 regulates the spatial localization of JA signaling in different plant organs. Indeed, JA-related genes showed differential expression patterns in leaves and flowers of transgenic plants.
Conclusions
Our results reveal that under stress conditions – for example, herbivore attacks -- stable JAZ proteins such as PpJAZ1 may alter JA signaling in different plant organs, resulting in autogamy as a reproductive assurance mechanism. This represents an additional mechanism by which plant hormone signaling can modulate a vital developmental process in response to stress.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0124-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0124-6
PMCID: PMC4364584  PMID: 25857534
JAZ proteins; Jasmonic acid; Autogamy; Cleistogamy; Peach; Floral display
43.  The dynamics of growth cone morphology 
BMC Biology  2015;13:10.
Background
Normal brain function depends on the development of appropriate patterns of neural connections. A critical role in guiding axons to their targets during neural development is played by neuronal growth cones. These have a complex and rapidly changing morphology; however, a quantitative understanding of this morphology, its dynamics and how these are related to growth cone movement, is lacking.
Results
Here we use eigenshape analysis (principal components analysis in shape space) to uncover the set of five to six basic shape modes that capture the most variance in growth cone form. By analysing how the projections of growth cones onto these principal modes evolve in time, we found that growth cone shape oscillates with a mean period of 30 min. The variability of oscillation periods and strengths between different growth cones was correlated with their forward movement, such that growth cones with strong, fast shape oscillations tended to extend faster. A simple computational model of growth cone shape dynamics based on dynamic microtubule instability was able to reproduce quantitatively both the mean and variance of oscillation periods seen experimentally, suggesting that the principal driver of growth cone shape oscillations may be intrinsic periodicity in cytoskeletal rearrangements.
Conclusions
Intrinsically driven shape oscillations are an important component of growth cone shape dynamics. More generally, eigenshape analysis has the potential to provide new quantitative information about differences in growth cone behaviour in different conditions.
doi:10.1186/s12915-015-0115-7
PMCID: PMC4353455  PMID: 25729914
Axon guidance; Neurite growth; Neural development; Eigenshape analysis; Shape analysis; Brain morphometry; Oscillations; Microtubules
44.  Keeping up with the ′omics: non-equilibrium models of gene regulation 
BMC Biology  2015;13:9.
Non-equilibrium processes are vital features of biological systems. Despite this universally accepted fact, gene regulation is typically formalized into models that assume thermodynamic equilibrium. As experimental evidence expands the repertoire of non-equilibrium genome regulatory mechanisms, theoreticians are challenged to devise general approaches to accommodate and suggest functions for non-equilibrium processes. Ahsendorf et al. provide one such framework, which is discussed in the context of the growing complexity of eukaryotic gene regulation.
doi:10.1186/s12915-015-0117-5
PMCID: PMC4321706  PMID: 25706645
45.  Open questions: seeking a holistic approach for mitochondrial research 
BMC Biology  2015;13:8.
In addition to their role as energy generators, mitochondria play critical and active roles in diverse signalling pathways, from immunity to cell survival and cell fate decisions. However, there remain many open questions and challenges as we work towards integrating this mighty organelle into established paradigms of cellular physiology.
doi:10.1186/s12915-015-0120-x
PMCID: PMC4318159  PMID: 25651813
46.  Aging and DNA methylation 
BMC Biology  2015;13:7.
In this Opinion article, we summarize how changes in DNA methylation occur during aging in mammals and discuss examples of how such events may contribute to the aging process. We explore mechanisms that could facilitate DNA methylation changes in a site-specific manner and highlight a model in which region-specific DNA hypermethylation during aging is facilitated in a competitive manner by destabilization of the Polycomb repressive complex.
doi:10.1186/s12915-015-0118-4
PMCID: PMC4311512  PMID: 25637097
47.  A role for Ras in inhibiting circular foraging behavior as revealed by a new method for time and cell-specific RNAi 
BMC Biology  2015;13:6.
Background
The nematode worm Caenorhabditis elegans, in which loss-of-function mutants and RNA interference (RNAi) models are available, is a model organism useful for analyzing effects of genes on various life phenomena, including behavior. In particular, RNAi is a powerful tool that enables time- or cell-specific knockdown via heat shock-inducible RNAi or cell-specific RNAi. However, conventional RNAi is insufficient for investigating pleiotropic genes with various sites of action and life stage-dependent functions.
Results
Here, we investigated the Ras gene for its role in exploratory behavior in C. elegans. We found that, under poor environmental conditions, mutations in the Ras-MAPK signaling pathway lead to circular locomotion instead of normal exploratory foraging. Spontaneous foraging is regulated by a neural circuit composed of three classes of neurons: IL1, OLQ, and RMD, and we found that Ras functions in this neural circuit to modulate the direction of locomotion. We further observed that Ras plays an essential role in the regulation of GLR-1 glutamate receptor localization in RMD neurons. To investigate the temporal- and cell-specific profiles of the functions of Ras, we developed a new RNAi method that enables simultaneous time- and cell-specific knockdown. In this method, one RNA strand is expressed by a cell-specific promoter and the other by a heat shock promoter, resulting in only expression of double-stranded RNA in the target cell when heat shock is induced. This technique revealed that control of GLR-1 localization in RMD neurons requires Ras at the adult stage. Further, we demonstrated the application of this method to other genes.
Conclusions
We have established a new RNAi method that performs simultaneous time- and cell-specific knockdown and have applied this to reveal temporal profiles of the Ras-MAPK pathway in the control of exploratory behavior under poor environmental conditions.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0114-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0114-8
PMCID: PMC4321700  PMID: 25603799
C. elegans; Exploratory behavior; Glutamate receptor; RNAi method; The Ras-MAPK pathway
48.  Morphogens, modeling and patterning the neural tube: an interview with James Briscoe 
BMC Biology  2015;13:5.
James Briscoe has a BSc in Microbiology and Virology (from the University of Warwick, UK) and a PhD in Molecular and Cellular Biology (from the Imperial Cancer Research Fund, London, now Cancer Research UK). He started working on the development of the neural tube in the lab of Tom Jessel as a postdoctoral fellow, establishing that there was graded sonic hedgehog signaling in the ventral neural tube. He is currently a group leader and Head of Division in Developmental Biology at the MRC National Institute for Medical Research (which will become part of the Francis Crick Institute in April 2015). He is working to understand the molecular and cellular mechanisms of graded signaling in the vertebrate neural tube.
We interviewed him about the development of ideas on morphogenetic gradients and his own work on modeling the development of the neural tube for our series on modeling in biology.
doi:10.1186/s12915-014-0105-1
PMCID: PMC4299813  PMID: 25600934
49.  Comparative RNA-Seq analysis reveals pervasive tissue-specific alternative polyadenylation in Caenorhabditis elegans intestine and muscles 
BMC Biology  2015;13:4.
Background
Tissue-specific RNA plasticity broadly impacts the development, tissue identity and adaptability of all organisms, but changes in composition, expression levels and its impact on gene regulation in different somatic tissues are largely unknown. Here we developed a new method, polyA-tagging and sequencing (PAT-Seq) to isolate high-quality tissue-specific mRNA from Caenorhabditis elegans intestine, pharynx and body muscle tissues and study changes in their tissue-specific transcriptomes and 3’UTRomes.
Results
We have identified thousands of novel genes and isoforms differentially expressed between these three tissues. The intestine transcriptome is expansive, expressing over 30% of C. elegans mRNAs, while muscle transcriptomes are smaller but contain characteristic unique gene signatures. Active promoter regions in all three tissues reveal both known and novel enriched tissue-specific elements, along with putative transcription factors, suggesting novel tissue-specific modes of transcription initiation. We have precisely mapped approximately 20,000 tissue-specific polyadenylation sites and discovered that about 30% of transcripts in somatic cells use alternative polyadenylation in a tissue-specific manner, with their 3’UTR isoforms significantly enriched with microRNA targets.
Conclusions
For the first time, PAT-Seq allowed us to directly study tissue specific gene expression changes in an in vivo setting and compare these changes between three somatic tissues from the same organism at single-base resolution within the same experiment. We pinpoint precise tissue-specific transcriptome rearrangements and for the first time link tissue-specific alternative polyadenylation to miRNA regulation, suggesting novel and unexplored tissue-specific post-transcriptional regulatory networks in somatic cells.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0116-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0116-6
PMCID: PMC4343181  PMID: 25601023
RNA-Seq; Tissue-specific mRNA; Elegans; Promoter; Transcription; mRNA-tagging; Transcriptome; 3’UTR; miRNAs; PAT-Seq
50.  A fast recoiling silk-like elastomer facilitates nanosecond nematocyst discharge 
BMC Biology  2015;13:3.
Background
The discharge of the Cnidarian stinging organelle, the nematocyst, is one of the fastest processes in biology and involves volume changes of the highly pressurised (150 bar) capsule of up to 50%. Hitherto, the molecular basis for the unusual biomechanical properties of nematocysts has been elusive, as their structure was mainly defined as a stress-resistant collagenous matrix.
Results
Here, we characterise Cnidoin, a novel elastic protein identified as a structural component of Hydra nematocysts. Cnidoin is expressed in nematocytes of all types and immunostainings revealed incorporation into capsule walls and tubules concomitant with minicollagens. Similar to spider silk proteins, to which it is related at sequence level, Cnidoin possesses high elasticity and fast coiling propensity as predicted by molecular dynamics simulations and quantified by force spectroscopy. Recombinant Cnidoin showed a high tendency for spontaneous aggregation to bundles of fibrillar structures.
Conclusions
Cnidoin represents the molecular factor involved in kinetic energy storage and release during the ultra-fast nematocyst discharge. Furthermore, it implies an early evolutionary origin of protein elastomers in basal metazoans.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-014-0113-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-014-0113-1
PMCID: PMC4321713  PMID: 25592740
Hydra; Nematocyst; Elastomer; Molecular dynamics; Single molecule force spectroscopy

Results 26-50 (935)