The Evolution of Cell Communication: The Road not Taken.

In the post-genomic era the complex problem of evolutionary biology can be tackled from the top-down, the bottom-up, or from the middle-out. Given the emergent and contingent nature of this process, we have chosen to take the latter approach, both as a mechanistic link to developmental biology and as a rational means of identifying signaling mechanisms based on their functional genomic significance. Using this approach, we have been able to configure a working model for lung evolution by reverse-engineering lung surfactant from the mammalian lung to the swim bladder of fish. Based on this archetypal cell-molecular model, we have reduced evolutionary biology to cell communication, starting with unicellular organisms communicating with the environment, followed by cell-cell communication to generate metazoa, culminating in the communication of genetic information between generations, i.e. reproduction. This model predicts the evolution of physiologic systems-including development, homeostasis, disease, regeneration/repair, and aging- as a logical consequence of biology reducing entropy. This approach provides a novel and robust way of formulating refutable, testable hypotheses to determine the ultimate origins and first principles of physiology, providing candidate genes for phenotypes hypothesized to have mediated evolutionary changes in structure and/or function. Ultimately, it will form the basis for predictive medicine and molecular bioethics, rather than merely showing associations between genes and pathology, which is an unequivocal Just So Story. In this new age of genomics, our reach must exceed our grasp

Comparative transcriptome analyses indicate molecular homology of zebrafish swimbladder and mammalian lung

10.1371/journal.pone.0024019PLoS ONE68

Phocid Seal Leptin: Tertiary Structure and Hydrophobic Receptor Binding Site Preservation during Distinct Leptin Gene Evolution

The cytokine hormone leptin is a key signalling molecule in many pathways that control physiological functions. Although leptin demonstrates structural conservation in mammals, there is evidence of positive selection in primates, lagomorphs and chiropterans. We previously reported that the leptin genes of the grey and harbour seals (phocids) have significantly diverged from other mammals. Therefore we further investigated the diversification of leptin in phocids, other marine mammals and terrestrial taxa by sequencing the leptin genes of representative species. Phylogenetic reconstruction revealed that leptin diversification was pronounced within the phocid seals with a high dN/dS ratio of 2.8, indicating positive selection. We found significant evidence of positive selection along the branch leading to the phocids, within the phocid clade, but not over the dataset as a whole. Structural predictions indicate that the individual residues under selection are away from the leptin receptor (LEPR) binding site. Predictions of the surface electrostatic potential indicate that phocid seal leptin is notably different to other mammalian leptins, including the otariids. Cloning the grey seal leptin binding domain of LEPR confirmed that this was structurally conserved. These data, viewed in toto, support a hypothesis that phocid leptin divergence is unlikely to have arisen by random mutation. Based upon these phylogenetic and structural assessments, and considering the comparative physiology and varying life histories among species, we postulate that the unique phocid diving behaviour has produced this selection pressure. The Phocidae includes some of the deepest diving species, yet have the least modified lung structure to cope with pressure and volume changes experienced at depth. Therefore, greater surfactant production is required to facilitate rapid lung re-inflation upon surfacing, while maintaining patent airways. We suggest that this additional surfactant requirement is met by the leptin pulmonary surfactant production pathway which normally appears only to function in the mammalian foetus

PDGF-Rα gene expression predicts proliferation, but PDGF-A suppresses transdifferentiation of neonatal mouse lung myofibroblasts

<p>Abstract</p> <p>Background</p> <p>Platelet-derived growth factor A (PDGF-A) signals solely through PDGF-Rα, and is required for fibroblast proliferation and transdifferentiation (fibroblast to myofibroblast conversion) during alveolar development, because <it>pdgfa</it>-null mice lack both myofibroblasts and alveoli. However, these PDGF-A-mediated mechanisms remain incompletely defined. At postnatal days 4 and 12 (P4 and P12), using mouse lung fibroblasts, we examined (a) how PDGF-Rα correlates with ki67 (proliferation marker) or alpha-smooth muscle actin (αSMA, myofibroblast marker) expression, and (b) whether PDGF-A directly affects αSMA or modifies stimulation by transforming growth factor beta (TGFβ).</p> <p>Methods</p> <p>Using flow cytometry we examined PDGF-Rα, αSMA and Ki67 in mice which express green fluorescent protein (GFP) as a marker for PDGF-Rα expression. Using real-time RT-PCR we quantified αSMA mRNA in cultured Mlg neonatal mouse lung fibroblasts after treatment with PDGF-A, and/or TGFβ.</p> <p>Results</p> <p>The intensity of GFP-fluorescence enabled us to distinguish three groups of fibroblasts which exhibited absent, lower, or higher levels of PDGF-Rα. At P4, more of the higher than lower PDGF-Rα + fibroblasts contained Ki67 (Ki67+), and Ki67+ fibroblasts predominated in the αSMA + but not the αSMA- population. By P12, Ki67+ fibroblasts comprised a minority in both the PDGF-Rα + and αSMA+ populations. At P4, most Ki67+ fibroblasts were PDGF-Rα + and αSMA- whereas at P12, most Ki67+ fibroblasts were PDGF-Rα- and αSMA-. More of the PDGF-Rα + than - fibroblasts contained αSMA at both P4 and P12. In the lung, proximate αSMA was more abundant around nuclei in cells expressing high than low levels of PDGF-Rα at both P4 and P12. Nuclear SMAD 2/3 declined from P4 to P12 in PDGF-Rα-, but not in PDGF-Rα + cells. In Mlg fibroblasts, αSMA mRNA increased after exposure to TGFβ, but declined after treatment with PDGF-A.</p> <p>Conclusion</p> <p>During both septal eruption (P4) and elongation (P12), alveolar PDGF-Rα may enhance the propensity of fibroblasts to transdifferentiate rather than directly stimulate αSMA, which preferentially localizes to non-proliferating fibroblasts. In accordance, PDGF-Rα more dominantly influences fibroblast proliferation at P4 than at P12. In the lung, TGFβ may overshadow the antagonistic effects of PDGF-A/PDGF-Rα signaling, enhancing αSMA-abundance in PDGF-Rα-expressing fibroblasts.</p

Lifelong testicular differentiation in Pleurodeles waltl (Amphibia, Caudata)

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The role of leptin in the respiratory system: an overview

Since its cloning in 1994, leptin has emerged in the literature as a pleiotropic hormone whose actions extend from immune system homeostasis to reproduction and angiogenesis. Recent investigations have identified the lung as a leptin responsive and producing organ, while extensive research has been published concerning the role of leptin in the respiratory system. Animal studies have provided evidence indicating that leptin is a stimulant of ventilation, whereas researchers have proposed an important role for leptin in lung maturation and development. Studies further suggest a significant impact of leptin on specific respiratory diseases, including obstructive sleep apnoea-hypopnoea syndrome, asthma, COPD and lung cancer. However, as new investigations are under way, the picture is becoming more complex. The scope of this review is to decode the existing data concerning the actions of leptin in the lung and provide a detailed description of leptin's involvement in the most common disorders of the respiratory system

Stem/progenitor cell populations resident in the lung and the role of stromal support in their maintenance and differentiation

Lungs are vital organs for respiration, being enabled by their complex three-dimensional organization [1]. Airway tubes bifurcate into millions of highly vascularized alveolar sacs, the alveoli, which are responsible for gas exchange. The gas exchange surface of the lungs makes up one of the largest surface areas of the human body. The alveoli receive air from the conducting airways, starting in the trachea, bifurcating into the bronchi and bronchioles, and ending in the terminal bronchioles, which divide into the alveolar ducts from which the alveoli arise. The aim of this chapter is to provide an overview of the progenitors in adult lung tissue and the regulation of their maintenance and differentiation by the microenvironment during lung developmental as well as repair processes, when developmental pathways are often reactivated. As most work has been done in mouse studies, the current knowledge from animal studies will be summarized and translated to what is known from human lungs. In order to understand the regenerative processes in the lung, we will first provide insight into the complex three-dimensional organization and composition of the lung, its function, and the processes involved in lung development.</p

The cell as the mechanistic basis for evolution.

The First Principles for Physiology originated in and emanate from the unicellular state of life. Viewing physiology as a continuum from unicellular to multicellular organisms provides fundamental insight to ontogeny and phylogeny as a functionally integral whole. Such mechanisms are most evident under conditions of physiologic stress; all of the molecular pathways that evolved in service to the vertebrate water-land transition aided and abetted the evolution of the vertebrate lung, for example. Reduction of evolution to cell biology has an important scientific feature—it is predictive. One implication of this perspective on evolution is the likelihood that it is the unicellular state that is actually the object of selection. By looking at the process of evolution from its unicellular origins, the causal relationships between genotype and phenotype are revealed, as are many other aspects of physiology and medicine that have remained anecdotal and counter-intuitive. Evolutionary development can best be considered as a cyclical, epigenetic, reiterative environmental assessment process, originating from the unicellular state, both forward and backward, to sustain and perpetuate unicellular homeostasis