Showing papers by "Stuart A. Newman published in 2017"

Sleeper cells: The stringent response and persistence in the Borreliella (Borrelia) burgdorferi enzootic cycle

Abstract: Infections with tick-transmitted Borreliella (Borrelia) burgdorferi, the cause of Lyme disease, represent an increasingly large public health problem in North America and Europe. The ability of these spirochetes to maintain themselves for extended periods of time in their tick vectors and vertebrate reservoirs is crucial for continuance of the enzootic cycle as well as for the increasing exposure of humans to them. The stringent response mediated by the alarmone (p)ppGpp has been determined to be a master regulator in B. burgdorferi. It modulates the expression of identified and unidentified open reading frames needed to deal with and overcome the many nutritional stresses and other challenges faced by the spirochete in ticks and animal reservoirs. The metabolic and morphologic changes resulting from activation of the stringent response in B. burgdorferi may also be involved in the recently described non-genetic phenotypic phenomenon of tolerance to otherwise lethal doses of antimicrobials and to other antimicrobial activities. It may thus constitute a linchpin in multiple aspects of infections with Lyme disease borrelia, providing a link between the micro-ecological challenges of its enzootic life-cycle and long-term residence in the tissues of its animal reservoirs, with the evolutionary side effect of potential persistence in incidental human hosts.

The evolutionary origin of digit patterning.

Abstract: The evolution of tetrapod limbs from paired fins has long been of interest to both evolutionary and developmental biologists. Several recent investigative tracks have converged to restructure hypotheses in this area. First, there is now general agreement that the limb skeleton is patterned by one or more Turing-type reaction–diffusion, or reaction–diffusion–adhesion, mechanism that involves the dynamical breaking of spatial symmetry. Second, experimental studies in finned vertebrates, such as catshark and zebrafish, have disclosed unexpected correspondence between the development of digits and the development of both the endoskeleton and the dermal skeleton of fins. Finally, detailed mathematical models in conjunction with analyses of the evolution of putative Turing system components have permitted formulation of scenarios for the stepwise evolutionary origin of patterning networks in the tetrapod limb. The confluence of experimental and biological physics approaches in conjunction with deepening understanding of the developmental genetics of paired fins and limbs has moved the field closer to understanding the fin-to-limb transition. We indicate challenges posed by still unresolved issues of novelty, homology, and the relation between cell differentiation and pattern formation.

Perspectives on Integrating Genetic and Physical Explanations of Evolution and Development: An Introduction to the Symposium.

Abstract: In the 20th century, genetic explanatory approaches became dominant in both developmental and evolutionary biological research. By contrast, physical approaches, which appeal to properties such as mechanical forces, were largely relegated to the margins, despite important advances in modeling. Recently, there have been renewed attempts to find balanced viewpoints that integrate both biological physics and molecular genetics into explanations of developmental and evolutionary phenomena. Here we introduce the 2017 SICB symposium "Physical and Genetic Mechanisms for Evolutionary Novelty" that was dedicated to exploring empirical cases where both biological physics and developmental genetic considerations are crucial. To further contextualize these case studies, we offer two theoretical frameworks for integrating genetic and physical explanations: combining complementary perspectives and comprehensive unification. We conclude by arguing that intentional reflection on conceptual questions about investigation, explanation, and integration is critical to achieving significant empirical and theoretical advances in our understanding of how novel forms originate across the tree of life.

Hes1 oscillations synchronize and refine condensation formation and patterning of the avian limb skeleton

Abstract: The tetrapod appendicular skeleton develops from a cartilage template that is prefigured by spatially patterned condensations of mesenchymal cells. The size and spacing of these condensations in the embryonic limbs of birds are mediated by a reaction-diffusion-adhesion network consisting of the matricellular proteins Gal-1A, Gal-8 and their glycosylated cell surface receptors. In cultures of limb precartilage mesenchymal cells we found that condensations appear simultaneously, which raised the question of how their formation is synchronized across distances greater than the characteristic wavelength of their spatial pattern. Since oscillatory dynamics of Hes1, a downstream target of Notch signaling, are involved in coordinating cell behavior during vertebrate somitogenesis, we explored whether they have a similar role in developing limb bud mesenchyme. Hes1 mRNA underwent oscillations with a periodicity of 6 hours during condensation formation in vitro. A mathematical model for the two-galectin pattern forming network, modified to incorporate periodicity in adhesive response of cells to Gal-1A, predicts that the spatiotemporal regularity of condensation formation is improved if the oscillator phase is synchronized across the culture. Treatment of cultures with DAPT, a pharmacological inhibitor of Notch signaling, led to elevation of both Gal-1A and -8 mRNA levels in vitro and in silico, suggesting that the Notch pathway is integral to the patterning network. DAPT predictably damped Hes1 oscillations and led to irregularly-sized and fused condensations in vitro. In developing limb buds in ovo, it led to spatially non-uniform Hes1 expression and fused and misshapen digits. Finally, the previously described sharpening effect of FGF2 on the condensation pattern was correlated with its enhancement of Hes1 synchronization. Together our experimental and computational results suggest that the two-galectin reaction-diffusion-adhesion network that patterns the avian limb skeleton is regulated by the Notch pathway. Moreover, global coordination of this pathway by synchronization of Hes1 oscillations across the tissue micromass in vitro or the digital plate in vivo refines and regularizes morphogenesis of the skeletal elements.