@article{12837, abstract = {As developing tissues grow in size and undergo morphogenetic changes, their material properties may be altered. Such changes result from tension dynamics at cell contacts or cellular jamming. Yet, in many cases, the cellular mechanisms controlling the physical state of growing tissues are unclear. We found that at early developmental stages, the epithelium in the developing mouse spinal cord maintains both high junctional tension and high fluidity. This is achieved via a mechanism in which interkinetic nuclear movements generate cell area dynamics that drive extensive cell rearrangements. Over time, the cell proliferation rate declines, effectively solidifying the tissue. Thus, unlike well-studied jamming transitions, the solidification uncovered here resembles a glass transition that depends on the dynamical stresses generated by proliferation and differentiation. Our finding that the fluidity of developing epithelia is linked to interkinetic nuclear movements and the dynamics of growth is likely to be relevant to multiple developing tissues.}, author = {Bocanegra, Laura and Singh, Amrita and Hannezo, Edouard B and Zagórski, Marcin P and Kicheva, Anna}, issn = {1745-2481}, journal = {Nature Physics}, pages = {1050--1058}, publisher = {Springer Nature}, title = {{Cell cycle dynamics control fluidity of the developing mouse neuroepithelium}}, doi = {10.1038/s41567-023-01977-w}, volume = {19}, year = {2023}, } @phdthesis{13081, abstract = {During development, tissues undergo changes in size and shape to form functional organs. Distinct cellular processes such as cell division and cell rearrangements underlie tissue morphogenesis. Yet how the distinct processes are controlled and coordinated, and how they contribute to morphogenesis is poorly understood. In our study, we addressed these questions using the developing mouse neural tube. This epithelial organ transforms from a flat epithelial sheet to an epithelial tube while increasing in size and undergoing morpho-gen-mediated patterning. The extent and mechanism of neural progenitor rearrangement within the developing mouse neuroepithelium is unknown. To investigate this, we per-formed high resolution lineage tracing analysis to quantify the extent of epithelial rear-rangement at different stages of neural tube development. We quantitatively described the relationship between apical cell size with cell cycle dependent interkinetic nuclear migra-tions (IKNM) and performed high cellular resolution live imaging of the neuroepithelium to study the dynamics of junctional remodeling. Furthermore, developed a vertex model of the neuroepithelium to investigate the quantitative contribution of cell proliferation, cell differentiation and mechanical properties to the epithelial rearrangement dynamics and validated the model predictions through functional experiments. Our analysis revealed that at early developmental stages, the apical cell area kinetics driven by IKNM induce high lev-els of cell rearrangements in a regime of high junctional tension and contractility. After E9.5, there is a sharp decline in the extent of cell rearrangements, suggesting that the epi-thelium transitions from a fluid-like to a solid-like state. We found that this transition is regulated by the growth rate of the tissue, rather than by changes in cell-cell adhesion and contractile forces. Overall, our study provides a quantitative description of the relationship between tissue growth, cell cycle dynamics, epithelia rearrangements and the emergent tissue material properties, and novel insights on how epithelial cell dynamics influences tissue morphogenesis.}, author = {Bocanegra, Laura}, issn = {2663 - 337X}, pages = {93}, publisher = {Institute of Science and Technology Austria}, title = {{Epithelial dynamics during mouse neural tube development}}, doi = {10.15479/at:ista:13081}, year = {2023}, } @article{14484, abstract = {Intercellular signaling molecules, known as morphogens, act at a long range in developing tissues to provide spatial information and control properties such as cell fate and tissue growth. The production, transport, and removal of morphogens shape their concentration profiles in time and space. Downstream signaling cascades and gene regulatory networks within cells then convert the spatiotemporal morphogen profiles into distinct cellular responses. Current challenges are to understand the diverse molecular and cellular mechanisms underlying morphogen gradient formation, as well as the logic of downstream regulatory circuits involved in morphogen interpretation. This knowledge, combining experimental and theoretical results, is essential to understand emerging properties of morphogen-controlled systems, such as robustness and scaling.}, author = {Kicheva, Anna and Briscoe, James}, issn = {1530-8995}, journal = {Annual Review of Cell and Developmental Biology}, pages = {91--121}, publisher = {Annual Reviews}, title = {{Control of tissue development by morphogens}}, doi = {10.1146/annurev-cellbio-020823-011522}, volume = {39}, year = {2023}, } @article{14774, abstract = {Morphogen gradients impart positional information to cells in a homogenous tissue field. Fgf8a, a highly conserved growth factor, has been proposed to act as a morphogen during zebrafish gastrulation. However, technical limitations have so far prevented direct visualization of the endogenous Fgf8a gradient and confirmation of its morphogenic activity. Here, we monitor Fgf8a propagation in the developing neural plate using a CRISPR/Cas9-mediated EGFP knock-in at the endogenous fgf8a locus. By combining sensitive imaging with single-molecule fluorescence correlation spectroscopy, we demonstrate that Fgf8a, which is produced at the embryonic margin, propagates by diffusion through the extracellular space and forms a graded distribution towards the animal pole. Overlaying the Fgf8a gradient curve with expression profiles of its downstream targets determines the precise input-output relationship of Fgf8a-mediated patterning. Manipulation of the extracellular Fgf8a levels alters the signaling outcome, thus establishing Fgf8a as a bona fide morphogen during zebrafish gastrulation. Furthermore, by hindering Fgf8a diffusion, we demonstrate that extracellular diffusion of the protein from the source is crucial for it to achieve its morphogenic potential.}, author = {Harish, Rohit K and Gupta, Mansi and Zöller, Daniela and Hartmann, Hella and Gheisari, Ali and Machate, Anja and Hans, Stefan and Brand, Michael}, issn = {1477-9129}, journal = {Development}, keywords = {Developmental Biology, Molecular Biology}, number = {19}, publisher = {The Company of Biologists}, title = {{Real-time monitoring of an endogenous Fgf8a gradient attests to its role as a morphogen during zebrafish gastrulation}}, doi = {10.1242/dev.201559}, volume = {150}, year = {2023}, } @article{13136, abstract = {Despite its fundamental importance for development, the question of how organs achieve their correct size and shape is poorly understood. This complex process requires coordination between the generation of cell mass and the morphogenetic mechanisms that sculpt tissues. These processes are regulated by morphogen signalling pathways and mechanical forces. Yet, in many systems, it is unclear how biochemical and mechanical signalling are quantitatively interpreted to determine the behaviours of individual cells and how they contribute to growth and morphogenesis at the tissue scale. In this review, we discuss the development of the vertebrate neural tube and somites as an example of the state of knowledge, as well as the challenges in understanding the mechanisms of tissue size control in vertebrate organogenesis. We highlight how the recent advances in stem cell differentiation and organoid approaches can be harnessed to provide new insights into this question.}, author = {Minchington, Thomas and Rus, Stefanie and Kicheva, Anna}, issn = {2452-3100}, journal = {Current Opinion in Systems Biology}, publisher = {Elsevier}, title = {{Control of tissue dimensions in the developing neural tube and somites}}, doi = {10.1016/j.coisb.2023.100459}, volume = {35}, year = {2023}, } @phdthesis{14323, abstract = {Morphogens are signaling molecules that are known for their prominent role in pattern formation within developing tissues. In addition to patterning, morphogens also control tissue growth. However, the underlying mechanisms are poorly understood. We studied the role of morphogens in regulating tissue growth in the developing vertebrate neural tube. In this system, opposing morphogen gradients of Shh and BMP establish the dorsoventral pattern of neural progenitor domains. Perturbations in these morphogen pathways result in alterations in tissue growth and cell cycle progression, however, it has been unclear what cellular process is affected. To address this, we analysed the rates of cell proliferation and cell death in mouse mutants in which signaling is perturbed, as well as in chick neural plate explants exposed to defined concentrations of signaling activators or inhibitors. Our results indicated that the rate of cell proliferation was not altered in these assays. By contrast, both the Shh and BMP signaling pathways had profound effects on neural progenitor survival. Our results indicate that these pathways synergise to promote cell survival within neural progenitors. Consistent with this, we found that progenitors within the intermediate region of the neural tube, where the combined levels of Shh and BMP are the lowest, are most prone to cell death when signaling activity is inhibited. In addition, we found that downregulation of Shh results in increased apoptosis within the roof plate, which is the dorsal source of BMP ligand production. This revealed a cross-interaction between the Shh and BMP morphogen signaling pathways that may be relevant for understanding how gradients scale in neural tubes with different overall sizes. We further studied the mechanism acting downstream of Shh in cell survival regulation using genetic and genomic approaches. We propose that Shh transcriptionally regulates a non-canonical apoptotic pathway. Altogether, our study points to a novel role of opposing morphogen gradients in tissue size regulation and provides new insights into complex interactions between Shh and BMP signaling gradients in the neural tube.}, author = {Kuzmicz-Kowalska, Katarzyna}, issn = {2663 - 337X}, pages = {151}, publisher = {Institute of Science and Technology Austria}, title = {{Regulation of neural progenitor survival by Shh and BMP in the developing spinal cord}}, doi = {10.15479/at:ista:14323}, year = {2023}, } @article{12245, abstract = {MicroRNAs (miRs) have an important role in tuning dynamic gene expression. However, the mechanism by which they are quantitatively controlled is unknown. We show that the amount of mature miR-9, a key regulator of neuronal development, increases during zebrafish neurogenesis in a sharp stepwise manner. We characterize the spatiotemporal profile of seven distinct microRNA primary transcripts (pri-mir)-9s that produce the same mature miR-9 and show that they are sequentially expressed during hindbrain neurogenesis. Expression of late-onset pri-mir-9-1 is added on to, rather than replacing, the expression of early onset pri-mir-9-4 and -9-5 in single cells. CRISPR/Cas9 mutation of the late-onset pri-mir-9-1 prevents the developmental increase of mature miR-9, reduces late neuronal differentiation and fails to downregulate Her6 at late stages. Mathematical modelling shows that an adaptive network containing Her6 is insensitive to linear increases in miR-9 but responds to stepwise increases of miR-9. We suggest that a sharp stepwise increase of mature miR-9 is created by sequential and additive temporal activation of distinct loci. This may be a strategy to overcome adaptation and facilitate a transition of Her6 to a new dynamic regime or steady state.}, author = {Soto, Ximena and Burton, Joshua and Manning, Cerys S. and Minchington, Thomas and Lea, Robert and Lee, Jessica and Kursawe, Jochen and Rattray, Magnus and Papalopulu, Nancy}, issn = {1477-9129}, journal = {Development}, keywords = {Developmental Biology, Molecular Biology}, number = {19}, publisher = {The Company of Biologists}, title = {{Sequential and additive expression of miR-9 precursors control timing of neurogenesis}}, doi = {10.1242/dev.200474}, volume = {149}, year = {2022}, } @article{9349, abstract = {The way in which interactions between mechanics and biochemistry lead to the emergence of complex cell and tissue organization is an old question that has recently attracted renewed interest from biologists, physicists, mathematicians and computer scientists. Rapid advances in optical physics, microscopy and computational image analysis have greatly enhanced our ability to observe and quantify spatiotemporal patterns of signalling, force generation, deformation, and flow in living cells and tissues. Powerful new tools for genetic, biophysical and optogenetic manipulation are allowing us to perturb the underlying machinery that generates these patterns in increasingly sophisticated ways. Rapid advances in theory and computing have made it possible to construct predictive models that describe how cell and tissue organization and dynamics emerge from the local coupling of biochemistry and mechanics. Together, these advances have opened up a wealth of new opportunities to explore how mechanochemical patterning shapes organismal development. In this roadmap, we present a series of forward-looking case studies on mechanochemical patterning in development, written by scientists working at the interface between the physical and biological sciences, and covering a wide range of spatial and temporal scales, organisms, and modes of development. Together, these contributions highlight the many ways in which the dynamic coupling of mechanics and biochemistry shapes biological dynamics: from mechanoenzymes that sense force to tune their activity and motor output, to collectives of cells in tissues that flow and redistribute biochemical signals during development.}, author = {Lenne, Pierre François and Munro, Edwin and Heemskerk, Idse and Warmflash, Aryeh and Bocanegra, Laura and Kishi, Kasumi and Kicheva, Anna and Long, Yuchen and Fruleux, Antoine and Boudaoud, Arezki and Saunders, Timothy E. and Caldarelli, Paolo and Michaut, Arthur and Gros, Jerome and Maroudas-Sacks, Yonit and Keren, Kinneret and Hannezo, Edouard B and Gartner, Zev J. and Stormo, Benjamin and Gladfelter, Amy and Rodrigues, Alan and Shyer, Amy and Minc, Nicolas and Maître, Jean Léon and Di Talia, Stefano and Khamaisi, Bassma and Sprinzak, David and Tlili, Sham}, issn = {1478-3975}, journal = {Physical biology}, number = {4}, publisher = {IOP Publishing}, title = {{Roadmap for the multiscale coupling of biochemical and mechanical signals during development}}, doi = {10.1088/1478-3975/abd0db}, volume = {18}, year = {2021}, } @article{7883, abstract = {All vertebrates have a spinal cord with dimensions and shape specific to their species. Yet how species‐specific organ size and shape are achieved is a fundamental unresolved question in biology. The formation and sculpting of organs begins during embryonic development. As it develops, the spinal cord extends in anterior–posterior direction in synchrony with the overall growth of the body. The dorsoventral (DV) and apicobasal lengths of the spinal cord neuroepithelium also change, while at the same time a characteristic pattern of neural progenitor subtypes along the DV axis is established and elaborated. At the basis of these changes in tissue size and shape are biophysical determinants, such as the change in cell number, cell size and shape, and anisotropic tissue growth. These processes are controlled by global tissue‐scale regulators, such as morphogen signaling gradients as well as mechanical forces. Current challenges in the field are to uncover how these tissue‐scale regulatory mechanisms are translated to the cellular and molecular level, and how regulation of distinct cellular processes gives rise to an overall defined size. Addressing these questions will help not only to achieve a better understanding of how size is controlled, but also of how tissue size is coordinated with the specification of pattern.}, author = {Kuzmicz-Kowalska, Katarzyna and Kicheva, Anna}, issn = {17597692}, journal = {Wiley Interdisciplinary Reviews: Developmental Biology}, publisher = {Wiley}, title = {{Regulation of size and scale in vertebrate spinal cord development}}, doi = {10.1002/wdev.383}, year = {2021}, } @article{7165, abstract = {Cell division, movement and differentiation contribute to pattern formation in developing tissues. This is the case in the vertebrate neural tube, in which neurons differentiate in a characteristic pattern from a highly dynamic proliferating pseudostratified epithelium. To investigate how progenitor proliferation and differentiation affect cell arrangement and growth of the neural tube, we used experimental measurements to develop a mechanical model of the apical surface of the neuroepithelium that incorporates the effect of interkinetic nuclear movement and spatially varying rates of neuronal differentiation. Simulations predict that tissue growth and the shape of lineage-related clones of cells differ with the rate of differentiation. Growth is isotropic in regions of high differentiation, but dorsoventrally biased in regions of low differentiation. This is consistent with experimental observations. The absence of directional signalling in the simulations indicates that global mechanical constraints are sufficient to explain the observed differences in anisotropy. This provides insight into how the tissue growth rate affects cell dynamics and growth anisotropy and opens up possibilities to study the coupling between mechanics, pattern formation and growth in the neural tube.}, author = {Guerrero, Pilar and Perez-Carrasco, Ruben and Zagórski, Marcin P and Page, David and Kicheva, Anna and Briscoe, James and Page, Karen M.}, issn = {1477-9129}, journal = {Development}, number = {23}, publisher = {The Company of Biologists}, title = {{Neuronal differentiation influences progenitor arrangement in the vertebrate neuroepithelium}}, doi = {10.1242/dev.176297}, volume = {146}, year = {2019}, } @inbook{37, abstract = {Developmental processes are inherently dynamic and understanding them requires quantitative measurements of gene and protein expression levels in space and time. While live imaging is a powerful approach for obtaining such data, it is still a challenge to apply it over long periods of time to large tissues, such as the embryonic spinal cord in mouse and chick. Nevertheless, dynamics of gene expression and signaling activity patterns in this organ can be studied by collecting tissue sections at different developmental stages. In combination with immunohistochemistry, this allows for measuring the levels of multiple developmental regulators in a quantitative manner with high spatiotemporal resolution. The mean protein expression levels over time, as well as embryo-to-embryo variability can be analyzed. A key aspect of the approach is the ability to compare protein levels across different samples. This requires a number of considerations in sample preparation, imaging and data analysis. Here we present a protocol for obtaining time course data of dorsoventral expression patterns from mouse and chick neural tube in the first 3 days of neural tube development. The described workflow starts from embryo dissection and ends with a processed dataset. Software scripts for data analysis are included. The protocol is adaptable and instructions that allow the user to modify different steps are provided. Thus, the procedure can be altered for analysis of time-lapse images and applied to systems other than the neural tube.}, author = {Zagórski, Marcin P and Kicheva, Anna}, booktitle = {Morphogen Gradients }, isbn = {978-1-4939-8771-9}, issn = {1064-3745}, pages = {47 -- 63}, publisher = {Springer Nature}, title = {{Measuring dorsoventral pattern and morphogen signaling profiles in the growing neural tube}}, doi = {10.1007/978-1-4939-8772-6_4}, volume = {1863}, year = {2018}, } @article{162, abstract = {Facial shape is the basis for facial recognition and categorization. Facial features reflect the underlying geometry of the skeletal structures. Here, we reveal that cartilaginous nasal capsule (corresponding to upper jaw and face) is shaped by signals generated by neural structures: brain and olfactory epithelium. Brain-derived Sonic Hedgehog (SHH) enables the induction of nasal septum and posterior nasal capsule, whereas the formation of a capsule roof is controlled by signals from the olfactory epithelium. Unexpectedly, the cartilage of the nasal capsule turned out to be important for shaping membranous facial bones during development. This suggests that conserved neurosensory structures could benefit from protection and have evolved signals inducing cranial cartilages encasing them. Experiments with mutant mice revealed that the genomic regulatory regions controlling production of SHH in the nervous system contribute to facial cartilage morphogenesis, which might be a mechanism responsible for the adaptive evolution of animal faces and snouts.}, author = {Kaucka, Marketa and Petersen, Julian and Tesarova, Marketa and Szarowska, Bara and Kastriti, Maria and Xie, Meng and Kicheva, Anna and Annusver, Karl and Kasper, Maria and Symmons, Orsolya and Pan, Leslie and Spitz, Francois and Kaiser, Jozef and Hovorakova, Maria and Zikmund, Tomas and Sunadome, Kazunori and Matise, Michael P and Wang, Hui and Marklund, Ulrika and Abdo, Hind and Ernfors, Patrik and Maire, Pascal and Wurmser, Maud and Chagin, Andrei S and Fried, Kaj and Adameyko, Igor}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Signals from the brain and olfactory epithelium control shaping of the mammalian nasal capsule cartilage}}, doi = {10.7554/eLife.34465}, volume = {7}, year = {2018}, } @misc{9838, abstract = {Facial shape is the basis for facial recognition and categorization. Facial features reflect the underlying geometry of the skeletal structures. Here we reveal that cartilaginous nasal capsule (corresponding to upper jaw and face) is shaped by signals generated by neural structures: brain and olfactory epithelium. Brain-derived Sonic Hedgehog (SHH) enables the induction of nasal septum and posterior nasal capsule, whereas the formation of a capsule roof is controlled by signals from the olfactory epithelium. Unexpectedly, the cartilage of the nasal capsule turned out to be important for shaping membranous facial bones during development. This suggests that conserved neurosensory structures could benefit from protection and have evolved signals inducing cranial cartilages encasing them. Experiments with mutant mice revealed that the genomic regulatory regions controlling production of SHH in the nervous system contribute to facial cartilage morphogenesis, which might be a mechanism responsible for the adaptive evolution of animal faces and snouts.}, author = {Kaucka, Marketa and Petersen, Julian and Tesarova, Marketa and Szarowska, Bara and Kastriti, Maria Eleni and Xie, Meng and Kicheva, Anna and Annusver, Karl and Kasper, Maria and Symmons, Orsolya and Pan, Leslie and Spitz, Francois and Kaiser, Jozef and Hovorakova, Maria and Zikmund, Tomas and Sunadome, Kazunori and Matise, Michael P and Wang, Hui and Marklund, Ulrika and Abdo, Hind and Ernfors, Patrik and Maire, Pascal and Wurmser, Maud and Chagin, Andrei S and Fried, Kaj and Adameyko, Igor}, publisher = {Dryad}, title = {{Data from: Signals from the brain and olfactory epithelium control shaping of the mammalian nasal capsule cartilage}}, doi = {10.5061/dryad.f1s76f2}, year = {2018}, } @article{314, abstract = {The interface of physics and biology pro-vides a fruitful environment for generatingnew concepts and exciting ways forwardto understanding living matter. Examplesof successful studies include the estab-lishment and readout of morphogen gra-dients during development, signal pro-cessing in protein and genetic networks,the role of fluctuations in determining thefates of cells and tissues, and collectiveeffects in proteins and in tissues. It is nothard to envision that significant further ad-vances will translate to societal benefitsby initiating the development of new de-vices and strategies for curing disease.However, research at the interface posesvarious challenges, in particular for youngscientists, and current institutions arerarely designed to facilitate such scientificprograms. In this Letter, we propose aninternational initiative that addressesthese challenges through the establish-ment of a worldwide network of platformsfor cross-disciplinary training and incuba-tors for starting new collaborations.}, author = {Bauer, Guntram and Fakhri, Nikta and Kicheva, Anna and Kondev, Jané and Kruse, Karsten and Noji, Hiroyuki and Riveline, Daniel and Saunders, Timothy and Thatta, Mukund and Wieschaus, Eric}, issn = {2405-4712}, journal = {Cell Systems}, number = {4}, pages = {400 -- 402}, publisher = {Cell Press}, title = {{The science of living matter for tomorrow}}, doi = {10.1016/j.cels.2018.04.003}, volume = {6}, year = {2018}, } @article{654, abstract = {In November 2016, developmental biologists, synthetic biologists and engineers gathered in Paris for a meeting called ‘Engineering the embryo’. The participants shared an interest in exploring how synthetic systems can reveal new principles of embryonic development, and how the in vitro manipulation and modeling of development using stem cells can be used to integrate ideas and expertise from physics, developmental biology and tissue engineering. As we review here, the conference pinpointed some of the challenges arising at the intersection of these fields, along with great enthusiasm for finding new approaches and collaborations.}, author = {Kicheva, Anna and Rivron, Nicolas}, issn = {09501991}, journal = {Development}, number = {5}, pages = {733 -- 736}, publisher = {Company of Biologists}, title = {{Creating to understand – developmental biology meets engineering in Paris}}, doi = {10.1242/dev.144915}, volume = {144}, year = {2017}, } @article{685, abstract = {By applying methods and principles from the physical sciences to biological problems, D'Arcy Thompson's On Growth and Form demonstrated how mathematical reasoning reveals elegant, simple explanations for seemingly complex processes. This has had a profound influence on subsequent generations of developmental biologists. We discuss how this influence can be traced through twentieth century morphologists, embryologists and theoreticians to current research that explores the molecular and cellular mechanisms of tissue growth and patterning, including our own studies of the vertebrate neural tube.}, author = {Briscoe, James and Kicheva, Anna}, issn = {09254773}, journal = {Mechanisms of Development}, pages = {26 -- 31}, publisher = {Elsevier}, title = {{The physics of development 100 years after D'Arcy Thompson's “on growth and form”}}, doi = {10.1016/j.mod.2017.03.005}, volume = {145}, year = {2017}, } @article{943, abstract = {Like many developing tissues, the vertebrate neural tube is patterned by antiparallel morphogen gradients. To understand how these inputs are interpreted, we measured morphogen signaling and target gene expression in mouse embryos and chick ex vivo assays. From these data, we derived and validated a characteristic decoding map that relates morphogen input to the positional identity of neural progenitors. Analysis of the observed responses indicates that the underlying interpretation strategy minimizes patterning errors in response to the joint input of noisy opposing gradients. We reverse-engineered a transcriptional network that provides a mechanistic basis for the observed cell fate decisions and accounts for the precision and dynamics of pattern formation. Together, our data link opposing gradient dynamics in a growing tissue to precise pattern formation.}, author = {Zagórski, Marcin P and Tabata, Yoji and Brandenberg, Nathalie and Lutolf, Matthias and Tkacik, Gasper and Bollenbach, Tobias and Briscoe, James and Kicheva, Anna}, issn = {00368075}, journal = {Science}, number = {6345}, pages = {1379 -- 1383}, publisher = {American Association for the Advancement of Science}, title = {{Decoding of position in the developing neural tube from antiparallel morphogen gradients}}, doi = {10.1126/science.aam5887}, volume = {356}, year = {2017}, } @article{1371, abstract = {Living cells can maintain their internal states, react to changing environments, grow, differentiate, divide, etc. All these processes are tightly controlled by what can be called a regulatory program. The logic of the underlying control can sometimes be guessed at by examining the network of influences amongst genetic components. Some associated gene regulatory networks have been studied in prokaryotes and eukaryotes, unveiling various structural features ranging from broad distributions of out-degrees to recurrent "motifs", that is small subgraphs having a specific pattern of interactions. To understand what factors may be driving such structuring, a number of groups have introduced frameworks to model the dynamics of gene regulatory networks. In that context, we review here such in silico approaches and show how selection for phenotypes, i.e., network function, can shape network structure.}, author = {Martin, Olivier and Krzywicki, André and Zagórski, Marcin P}, journal = {Physics of Life Reviews}, pages = {124 -- 158}, publisher = {Elsevier}, title = {{Drivers of structural features in gene regulatory networks: From biophysical constraints to biological function}}, doi = {10.1016/j.plrev.2016.06.002}, volume = {17}, year = {2016}, } @article{1373, author = {Martin, Olivier and Zagórski, Marcin P}, journal = {Physics of Life Reviews}, pages = {168 -- 171}, publisher = {Elsevier}, title = {{Network architectures and operating principles. Reply to comments on "Drivers of structural features in gene regulatory networks: From biophysical constraints to biological function"}}, doi = {10.1016/j.plrev.2016.06.006}, volume = {17}, year = {2016}, } @article{1167, abstract = {Evolutionary pathways describe trajectories of biological evolution in the space of different variants of organisms (genotypes). The probability of existence and the number of evolutionary pathways that lead from a given genotype to a better-adapted genotype are important measures of accessibility of local fitness optima and the reproducibility of evolution. Both quantities have been studied in simple mathematical models where genotypes are represented as binary sequences of two types of basic units, and the network of permitted mutations between the genotypes is a hypercube graph. However, it is unclear how these results translate to the biologically relevant case in which genotypes are represented by sequences of more than two units, for example four nucleotides (DNA) or 20 amino acids (proteins), and the mutational graph is not the hypercube. Here we investigate accessibility of the best-adapted genotype in the general case of K > 2 units. Using computer generated and experimental fitness landscapes we show that accessibility of the global fitness maximum increases with K and can be much higher than for binary sequences. The increase in accessibility comes from the increase in the number of indirect trajectories exploited by evolution for higher K. As one of the consequences, the fraction of genotypes that are accessible increases by three orders of magnitude when the number of units K increases from 2 to 16 for landscapes of size N ∼ 106genotypes. This suggests that evolution can follow many different trajectories on such landscapes and the reconstruction of evolutionary pathways from experimental data might be an extremely difficult task.}, author = {Zagórski, Marcin P and Burda, Zdzisław and Wacław, Bartłomiej}, journal = {PLoS Computational Biology}, number = {12}, publisher = {Public Library of Science}, title = {{Beyond the hypercube evolutionary accessibility of fitness landscapes with realistic mutational networks}}, doi = {10.1371/journal.pcbi.1005218}, volume = {12}, year = {2016}, } @misc{9866, author = {Zagórski, Marcin P and Burda, Zdzisław and Wacław, Bartłomiej}, publisher = {Public Library of Science}, title = {{ZIP-archived directory containing all data and computer programs}}, doi = {10.1371/journal.pcbi.1005218.s009}, year = {2016}, }