Branch Mode Selection during Early Lung Development

Many organs of higher organisms, such as the vascular system, lung, kidney, pancreas, liver and glands, are heavily branched structures. The branching process during lung development has been studied in great detail and is remarkably stereotyped. The branched tree is generated by the sequential, non-random use of three geometrically simple modes of branching (domain branching, planar and orthogonal bifurcation). While many regulatory components and local interactions have been defined an integrated understanding of the regulatory network that controls the branching process is lacking. We have developed a deterministic, spatio-temporal differential-equation based model of the core signaling network that governs lung branching morphogenesis. The model focuses on the two key signaling factors that have been identified in experiments, fibroblast growth factor (FGF10) and sonic hedgehog (SHH) as well as the SHH receptor patched (Ptc). We show that the reported biochemical interactions give rise to a Schnakenberg-type Turing patterning mechanisms that allows us to reproduce experimental observations in wildtype and mutant mice. The kinetic parameters as well as the domain shape are based on experimental data where available. The developed model is robust to small absolute and large relative changes in the parameter values. At the same time there is a strong regulatory potential in that the switching between branching modes can be achieved by targeted changes in the parameter values. We note that the sequence of different branching events may also be the result of different growth speeds: fast growth triggers lateral branching while slow growth favours bifurcations in our model. We conclude that the FGF10-SHH-Ptc1 module is sufficient to generate pattern that correspond to the observed branching modesComment: Initially published at PLoS Comput Bio

Uniparental Genetic Heritage of Belarusians: Encounter of Rare Middle Eastern Matrilineages with a Central European Mitochondrial DNA Pool

Ethnic Belarusians make up more than 80% of the nine and half million people inhabiting the Republic of Belarus. Belarusians together with Ukrainians and Russians represent the East Slavic linguistic group, largest both in numbers and territory, inhabiting East Europe alongside Baltic-, Finno-Permic- and Turkic-speaking people. Till date, only a limited number of low resolution genetic studies have been performed on this population. Therefore, with the phylogeographic analysis of 565 Y-chromosomes and 267 mitochondrial DNAs from six well covered geographic sub-regions of Belarus we strove to complement the existing genetic profile of eastern Europeans. Our results reveal that around 80% of the paternal Belarusian gene pool is composed of R1a, I2a and N1c Y-chromosome haplogroups – a profile which is very similar to the two other eastern European populations – Ukrainians and Russians. The maternal Belarusian gene pool encompasses a full range of West Eurasian haplogroups and agrees well with the genetic structure of central-east European populations. Our data attest that latitudinal gradients characterize the variation of the uniparentally transmitted gene pools of modern Belarusians. In particular, the Y-chromosome reflects movements of people in central-east Europe, starting probably as early as the beginning of the Holocene. Furthermore, the matrilineal legacy of Belarusians retains two rare mitochondrial DNA haplogroups, N1a3 and N3, whose phylogeographies were explored in detail after de novo sequencing of 20 and 13 complete mitogenomes, respectively, from all over Eurasia. Our phylogeographic analyses reveal that two mitochondrial DNA lineages, N3 and N1a3, both of Middle Eastern origin, might mark distinct events of matrilineal gene flow to Europe: during the mid-Holocene period and around the Pleistocene-Holocene transition, respectively

Ionic liquid electrolytes for safer and more reliable sodium battery systems

Na+-conducting, binary electrolytic mixtures, based on 1-ethyl-3-methyl-imidazolium, trimethyl-butyl-ammonium, and N-alkyl-N-methyl-piperidinium ionic liquid (IL) families, were designed and investigated. The anions were selected among the per(fluoroalkylsulfonyl)imide families. Sodium bis(trifluoromethylsulfonyl)imide, NaTFSI, was selected as the salt. The NaTFSI-IL electrolytes, addressed to safer sodium battery systems, were studied and compared in terms of ionic conductivity and thermal stability as a function of the temperature, the nature of the anion and the cation aliphatic side chain length. Room temperature conductivities of interest for sodium batteries, i.e., largely overcoming 10-4 or 10-3 S cm-1, are displayed. Similar conduction values are exhibited by the EMI-based samples even below -10 °C, making these electrolyte mixtures potentially appealing also for low temperature applications. The NaTFSI-IL electrolytes, with the exception of the FSI-ones, are found to be thermally stable up to 275 °C, depending on the nature of the cation and/or anion, thus extending their applicability above 100 °C and remarkably increasing the reliability and safety of the final device, especially in the case of prolonged overheating

Canonical wnt signaling activity in early stages of chick lung development

Wnt signaling pathway is an essential player during vertebrate embryonic development which has been associated with several developmental processes such as gastrulation, body axis formation and morphogenesis of numerous organs, namely the lung. Wnt proteins act through specific transmembrane receptors, which activate intracellular pathways that regulate cellular processes such as cell proliferation, differentiation and death. Morphogenesis of the fetal lung depends on epithelial-mesenchymal interactions that are governed by several growth and transcription factors that regulate cell proliferation, fate, migration and differentiation. This process is controlled by different signaling pathways such as FGF, Shh and Wnt among others. Wnt signaling is recognized as a key molecular player in mammalian pulmonary development but little is known about its function in avian lung development. The present work characterizes, for the first time, the expression pattern of several Wnt signaling members, such as wnt-1, wnt-2b, wnt-3a, wnt-5a, wnt-7b, wnt-8b, wnt-9a, lrp5, lrp6, sfrp1, dkk1, β-catenin and axin2 at early stages of chick lung development. In general, their expression is similar to their mammalian counterparts. By assessing protein expression levels of active/total β-catenin and phospho-LRP6/LRP6 it is revealed that canonical Wnt signaling is active in this embryonic tissue. In vitro inhibition studies were performed in order to evaluate the function of Wnt signaling pathway in lung branching. Lung explants treated with canonical Wnt signaling inhibitors (FH535 and PK115-584) presented an impairment of secondary branch formation after 48 h of culture along with a decrease in axin2 expression levels. Branching analysis confirmed this inhibition. Wnt-FGF crosstalk assessment revealed that this interaction is preserved in the chick lung. This study demonstrates that Wnt signaling is crucial for precise chick lung branching and further supports the avian lung as a good model for branching studies since it recapitulates early mammalian pulmonary development.Rute S. Moura was supported by a grant of ON.2 SR&TD Integrated Program (N-01-01-0124-01-07), ref: UMINHO/BPD/31/2013. The funders had no role in study design, data collection and analysis

Characterization of endogenous players in Fibroblast Growth Factor‐regulated functions of hypothalamic tanycytes and energy‐balance nuclei

The mammalian hypothalamus regulates key homeostatic and neuroendocrine functions ranging from circadian rhythm and energy‐balance to growth and reproductive cycles via the hypothalamo‐pituitary and hypothalamo‐thyroid axes. In addition to its neurons, tanycytes are taking centre stage in the short and long term augmentation and integration of diverse hypothalamic functions, but the genetic regulators and mediators of their involvement are poorly understood. Exogenous interventions have implicated Fibroblast growth factor (FGF) signalling, but the focal point of FGF action and any role for putative endogenous players also remains elusive. We carried out a comprehensive high‐resolution screen of FGF signalling pathway mediators and modifiers using a combination of in situ hybridization, immunolabelling and transgenic reporter mice, to map their spatial distribution in the adult hypothalamus. Our findings suggest that beta tanycytes are the likely focal point of exogenous and endogenous FGF action in the third ventricular wall, utilising FGF‐receptors (FGFRs) ‐1 and ‐2 IIIc isoforms, but not FGFR3. Key IIIc‐activating endogenous ligands include FGFs 1, 2, 9 and 18, which are expressed by a subset of ependymal and parenchymal cells. In the parenchymal compartment, FGFRs 1‐3 show divergent patterns, with FGFR1 predominant in neuronal nuclei and FGFR3 expression being associated with glial cell function. Intracrine FGFs are also present, suggestive of multiple modes of FGF function. Our findings provide a testable framework for understanding the complex role of FGFs in regulating the metabolic endocrine and neurogenic functions of hypothalamus in vivo

Retinoic acid regulates avian lung branching through a molecular network

Retinoic acid (RA) is of major importance during vertebrate embryonic development and its levels need to be strictly regulated otherwise congenital malformations will develop. Through the action of specific nuclear receptors, named RAR/RXR, RA regulates the expression of genes that eventually influence proliferation and tissue patterning. RA has been described as crucial for different stages of mammalian lung morphogenesis, and as part of a complex molecular network that contributes to precise organogenesis; nonetheless, nothing is known about its role in avian lung development. The current report characterizes, for the first time, the expression pattern of RA signaling members (stra6, raldh2, raldh3, cyp26a1, rar alpha, and rar beta) and potential RA downstream targets (sox2, sox9, meis1, meis2, tgf beta 2, and id2) by in situ hybridization. In the attempt of unveiling the role of RA in chick lung branching, in vitro lung explants were performed. Supplementation studies revealed that RA stimulates lung branching in a dose-dependent manner. Moreover, the expression levels of cyp26a1, sox2, sox9, rar beta, meis2, hoxb5, tgf beta 2, id2, fgf10, fgfr2, and shh were evaluated after RA treatment to disclose a putative molecular network underlying RA effect. In situ hybridization analysis showed that RA is able to alter cyp26a1, sox9, tgf beta 2, and id2 spatial distribution; to increase rar beta, meis2, and hoxb5 expression levels; and has a very modest effect on sox2, fgf10, fgfr2, and shh expression levels. Overall, these findings support a role for RA in the proximal-distal patterning and branching morphogenesis of the avian lung and reveal intricate molecular interactions that ultimately orchestrate branching morphogenesis.The authors would like to thank Ana Lima for slide sectioning and Rita Lopes for contributing to the initiation of this project. This work has been funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the Project POCI-01-0145-FEDER-007038; and by the Project NORTE-01-0145- FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio

Lung epithelial stem cells and their niches : Fgf10 takes center stage

Throughout life adult animals crucially depend on stem cell populations to maintain and repair their tissues to ensure life-long organ function. Stem cells are characterized by their capacity to extensively self-renew and give rise to one or more differentiated cell types. These powerful stem cell properties are key to meet the changing demand for tissue replacement during normal lung homeostasis and regeneration after lung injury. Great strides have been made over the last few years to identify and characterize lung epithelial stem cells as well as their lineage relationships. Unfortunately, knowledge on what regulates the behavior and fate specification of lung epithelial stem cells is still limited, but involves communication with their microenvironment or niche, a local tissue environment that hosts and influences the behaviors or characteristics of stem cells and that comprises other cell types and extracellular matrix. As such, an intimate and dynamic epithelial-mesenchymal cross-talk, which is also essential during lung development, is required for normal homeostasis and to mount an appropriate regenerative response after lung injury. Fibroblast growth factor 10 (Fgf10) signaling in particular seems to be a well-conserved signaling pathway governing epithelial-mesenchymal interactions during lung development as well as between different adult lung epithelial stem cells and their niches. On the other hand, disruption of these reciprocal interactions leads to a dysfunctional epithelial stem cell-niche unit, which may culminate in chronic lung diseases such as chronic obstructive pulmonary disease (COPD), chronic asthma and idiopathic pulmonary fibrosis (IPF)

Shape Self-Regulation in Early Lung Morphogenesis

The arborescent architecture of mammalian conductive airways results from the repeated branching of lung endoderm into surrounding mesoderm. Subsequent lung’s striking geometrical features have long raised the question of developmental mechanisms involved in morphogenesis. Many molecular actors have been identified, and several studies demonstrated the central role of Fgf10 and Shh in growth and branching. However, the actual branching mechanism and the way branching events are organized at the organ scale to achieve a self-avoiding tree remain to be understood through a model compatible with evidenced signaling. In this paper we show that the mere diffusion of FGF10 from distal mesenchyme involves differential epithelial proliferation that spontaneously leads to branching. Modeling FGF10 diffusion from sub-mesothelial mesenchyme where Fgf10 is known to be expressed and computing epithelial and mesenchymal growth in a coupled manner, we found that the resulting laplacian dynamics precisely accounts for the patterning of FGF10-induced genes, and that it spontaneously involves differential proliferation leading to a self-avoiding and space-filling tree, through mechanisms that we detail. The tree’s fine morphological features depend on the epithelial growth response to FGF10, underlain by the lung’s complex regulatory network. Notably, our results suggest that no branching information has to be encoded and that no master routine is required to organize branching events at the organ scale. Despite its simplicity, this model identifies key mechanisms of lung development, from branching to organ-scale organization, and could prove relevant to the development of other branched organs relying on similar pathways

A Virgo Environmental Survey Tracing Ionised Gas Emission (VESTIGE) XV. The Halpha luminosity function of the Virgo cluster

We use a complete set of deep narrow-band imaging data for 384 galaxies gathered during the VESTIGE survey to derive the first Halpha luminosity function (LF) of the Virgo cluster within R200. The data allow us to cover the whole dynamic range of the Halpha LF (10^36<LHa<10^42 erg s^-1). After they are corrected for [NII] contamination and dust attenuation, the data are used to derive the SFR function in the range 10^-4<SFR<10 Mo yr^-1. These LF are compared to those derived at other frequencies or using different tracers of star formation in Virgo, in other nearby and high-z clusters, in the field, and to those predicted by the IllustrisTNG cosmological hydrodynamical simulations. The Halpha LF of the Virgo cluster is fairly flat (a=-1.07) in the range 10^38.5<LHa<10^40.5 erg s^-1, and it abruptly decreases at lower luminosities. When compared to those derived for other nearby clusters and for the field, the slope and the characteristic luminosity of the Schechter function change as a function of the dynamical mass of the system, of the temperature of the X-rays gas, and of the dynamical pressure exerted on the interstellar medium of galaxies moving at high velocity within the intracluster medium. All these trends can be explained in a scenario in which the activity of SF is reduced in massive clusters due to their hydrodynamical interaction with the surrounding medium, suggesting once again that ram-pressure stripping is the dominant mechanism affecting galaxy evolution in local clusters of dynamical mass M200>10^14 Mo. The comparison with the IllustrisTNG cosmological hydrodynamical simulations shows a more pronounced decrease at the faint end of the distribution. If Virgo is representative of typical nearby clusters of similar mass, this difference suggests that the stripping process in simulated galaxies in these environments is more efficient than observed.Comment: Accepted for publication on A&