@phdthesis{20393, author = {Kishi, Kasumi}, issn = {2663-337X}, pages = {102}, publisher = {Institute of Science and Technology Austria}, title = {{Regulation of notochord and floor plate size during mouse development}}, doi = {10.15479/AT-ISTA-20393}, year = {2025}, } @phdthesis{19763, abstract = {Pattern formation in developing organs is controlled by morphogens. These signalling molecules form concentration gradients across tissues, thereby providing positional information that instructs the pattern of cell differentiation. Morphogen gradients are highly dynamic in space and time. Many factors such as morphogen production, spreading, degradation, cellular rearrangements and others could contribute to changes in the gradient shape, yet how the spatiotemporal signalling dynamics arise in many systems is still unclear. We studied the dynamics of morphogen signalling and tissue patterning in the developing vertebrate neural tube. In this system, neural crest, roof plate and distinct dorsal progenitor subtypes are specified in a spatially and temporally ordered manner in response to dorsal-toventral gradients of BMP and WNT signalling activity. How the BMP and WNT gradients are established and interpreted to ensure ordered cell specification is poorly understood. To address this question, we developed a 2D embryonic stem cell differentiation system that captures key features of dorsal neural tube development. In this system, differentiated colonies display remarkable self-organised pattern formation in response to uniformly applied BMP ligand. We established a method of differentiating the colonies using microfabricated stencils, which allowed us to control the initial size and shape of colonies without confining cell migration and colony growth. This led to highly reproducible pattern formation that facilitates quantification. Using this approach, we observed striking two-phase temporal dynamics of BMP signalling in our colonies: a BMP gradient rapidly forms from the periphery to the centre of colonies, subsequently disappears and is re-established again in the second phase. By combining our quantitative data with a data-driven theoretical model, we uncovered a temporal relay mechanism that underlies this biphasic BMP signalling dynamics. The first signalling phase is controlled by fast tissue-autonomous negative feedback that restricts the duration of the initial response to BMP. The early BMP activity gradient moreover controls the spatial organisation of the cell type pattern: the absence of a first phase results in disordered cell type pattern. The second phase is controlled by slow positive regulation of BMP signalling by the transcription factor LMX1A, a key regulator of roof plate identity. WNT promotes the second phase of BMP signalling via positive feedback on LMX1A. Altogether, the mechanism that we uncovered ensures the coupling of sequential developmental events, making pattern formation spatially and temporally organised. Furthermore, this mechanism allows the BMP signalling pathway to be reused in different contexts – first for the establishment of the neural plate border, and subsequently for dorsal neural progenitor patterning. Our study supports a general developmental principle in which multiple morphogens interact with transcriptional networks resulting in complex spatiotemporal signalling dynamics that ultimately drive organised pattern formation.}, author = {Rus, Stefanie}, issn = {2663-337X}, pages = {129}, publisher = {Institute of Science and Technology Austria}, title = {{Dynamics of morphogen signalling and cell fate decisions in the dorsal neural tube}}, doi = {10.15479/AT-ISTA-19763}, year = {2025}, } @article{18807, abstract = {Developing tissues interpret dynamic changes in morphogen activity to generate cell type diversity. To quantitatively study bone morphogenetic protein (BMP) signaling dynamics in the mouse neural tube, we developed an embryonic stem cell differentiation system tailored for growing tissues. Differentiating cells form striking self-organized patterns of dorsal neural tube cell types driven by sequential phases of BMP signaling that are observed both in vitro and in vivo. Data-driven biophysical modeling showed that these dynamics result from coupling fast negative feedback with slow positive regulation of signaling by the specification of an endogenous BMP source. Thus, in contrast to relays that propagate morphogen signaling in space, we identify a BMP signaling relay that operates in time. This mechanism allows for a rapid initial concentration-sensitive response that is robustly terminated, thereby regulating balanced sequential cell type generation. Our study provides an experimental and theoretical framework to understand how signaling dynamics are exploited in developing tissues.}, author = {Rus, Stefanie and Brückner, David and Minchington, Thomas and Greunz, Martina and Merrin, Jack and Hannezo, Edouard B and Kicheva, Anna}, issn = {1534-5807}, journal = {Developmental Cell}, number = {4}, pages = {567--580}, publisher = {Elsevier}, title = {{Self-organized pattern formation in the developing mouse neural tube by a temporal relay of BMP signaling}}, doi = {10.1016/j.devcel.2024.10.024}, volume = {60}, year = {2025}, } @article{18481, abstract = {A tight regulation of morphogen production is key for morphogen gradient formation and thereby for reproducible and organised organ development. Although many genetic interactions involved in the establishment of morphogen production domains are known, the biophysical mechanisms of morphogen source formation are poorly understood. Here we addressed this by focusing on the morphogen Sonic hedgehog (Shh) in the vertebrate neural tube. Shh is produced by the adjacently located notochord and by the floor plate of the neural tube. Using a data-constrained computational screen, we identified different possible mechanisms by which floor plate formation can occur, only one of which is consistent with experimental data. In this mechanism, the floor plate is established rapidly in response to Shh from the notochord and the dynamics of regulatory interactions within the neural tube. In this process, uniform activators and Shh-dependent repressors are key for establishing the floor plate size. Subsequently, the floor plate becomes insensitive to Shh and increases in size due to tissue growth, leading to scaling of the floor plate with neural tube size. In turn, this results in scaling of the Shh amplitude with tissue growth. Thus, this mechanism ensures a separation of time scales in floor plate formation, so that the floor plate domain becomes growth-dependent after an initial rapid establishment phase. Our study raises the possibility that the time scale separation between specification and growth might be a common strategy for scaling the morphogen gradient amplitude in growing organs. The model that we developed provides a new opportunity for quantitative studies of morphogen source formation in growing tissues.}, author = {Ho, Richard D.J.G. and Kishi, Kasumi and Majka, Maciej and Kicheva, Anna and Zagórski, Marcin P}, issn = {1553-7358}, journal = {PLoS Computational Biology}, publisher = {Public Library of Science}, title = {{Dynamics of morphogen source formation in a growing tissue}}, doi = {10.1371/journal.pcbi.1012508}, volume = {20}, year = {2024}, } @article{18902, author = {Zagorski, Marcin and Brandenberg, Nathalie and Lutolf, Matthias and Tkačik, Gašper and Bollenbach, Mark Tobias and Briscoe, James and Kicheva, Anna}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Assessing the precision of morphogen gradients in neural tube development}}, doi = {10.1038/s41467-024-45148-8}, volume = {15}, year = {2024}, } @article{17148, abstract = {During neural tube (NT) development, the notochord induces an organizer, the floorplate, which secretes Sonic Hedgehog (SHH) to pattern neural progenitors. Conversely, NT organoids (NTOs) from embryonic stem cells (ESCs) spontaneously form floorplates without the notochord, demonstrating that stem cells can self-organize without embryonic inducers. Here, we investigated floorplate self-organization in clonal mouse NTOs. Expression of the floorplate marker FOXA2 was initially spatially scattered before resolving into multiple clusters, which underwent competition and sorting, resulting in a stable “winning” floorplate. We identified that BMP signaling governed long-range cluster competition. FOXA2+ clusters expressed BMP4, suppressing FOXA2 in receiving cells while simultaneously expressing the BMP-inhibitor NOGGIN, promoting cluster persistence. Noggin mutation perturbed floorplate formation in NTOs and in the NT in vivo at mid/hindbrain regions, demonstrating how the floorplate can form autonomously without the notochord. Identifying the pathways governing organizer self-organization is critical for harnessing the developmental plasticity of stem cells in tissue engineering.}, author = {Krammer, Teresa and Stuart, Hannah T. and Gromberg, Elena and Ishihara, Keisuke and Cislo, Dillon and Melchionda, Manuela and Becerril Perez, Fernando and Wang, Jingkui and Costantini, Elena and Rus, Stefanie and Arbanas, Laura and Hörmann, Alexandra and Neumüller, Ralph A. and Elvassore, Nicola and Siggia, Eric and Briscoe, James and Kicheva, Anna and Tanaka, Elly M.}, issn = {1878-1551}, journal = {Developmental Cell}, number = {15}, pages = {1940--1953.e10}, publisher = {Elsevier}, title = {{Mouse neural tube organoids self-organize floorplate through BMP-mediated cluster competition}}, doi = {10.1016/j.devcel.2024.04.021}, volume = {59}, year = {2024}, } @article{18601, abstract = {Geometrically controlled stem cell differentiation promotes reproducible pattern formation. Here, we present a protocol to fabricate elastomeric stencils for patterned stem cell differentiation. We describe procedures for using photolithography to produce molds, followed by molding polydimethylsiloxane (PDMS) to obtain stencils with through holes. We then provide instructions for culturing cells on stencils and, finally, removing stencils to allow colony growth and cell migration. This approach yields reproducible two-dimensional organoids tailored for quantitative studies of growth and pattern formation. For complete details on the use and execution of this protocol, please refer to Lehr et al.1}, author = {Rus, Stefanie and Merrin, Jack and Kulig, Monika Aleksandra and Minchington, Thomas and Kicheva, Anna}, issn = {2666-1667}, journal = {STAR Protocols}, number = {4}, publisher = {Elsevier}, title = {{Protocol for fabricating elastomeric stencils for patterned stem cell differentiation}}, doi = {10.1016/j.xpro.2024.103187}, volume = {5}, year = {2024}, } @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{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}, } @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{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}, } @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{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{15262, abstract = {The Hunchback (Hb) transcription factor is crucial for anterior-posterior patterning of the Drosophila embryo. The maternal hb mRNA acts as a paradigm for translational regulation due to its repression in the posterior of the embryo. However, little is known about the translatability of zygotically transcribed hb mRNAs. Here, we adapt the SunTag system, developed for imaging translation at single-mRNA resolution in tissue culture cells, to the Drosophila embryo to study the translation dynamics of zygotic hb mRNAs. Using single-molecule imaging in fixed and live embryos, we provide evidence for translational repression of zygotic SunTag-hb mRNAs. Whereas the proportion of SunTag-hb mRNAs translated is initially uniform, translation declines from the anterior over time until it becomes restricted to a posterior band in the expression domain. We discuss how regulated hb mRNA translation may help establish the sharp Hb expression boundary, which is a model for precision and noise during developmental patterning. Overall, our data show how use of the SunTag method on fixed and live embryos is a powerful combination for elucidating spatiotemporal regulation of mRNA translation in Drosophila.}, author = {Vinter, Daisy J. and Hoppe, Caroline and Minchington, Thomas and Sutcliffe, Catherine and Ashe, Hilary L.}, issn = {1477-9129}, journal = {Development}, keywords = {Developmental Biology, Molecular Biology}, number = {18}, publisher = {The Company of Biologists}, title = {{Dynamics of hunchback translation in real-time and at single-mRNA resolution in the Drosophila embryo}}, doi = {10.1242/dev.196121}, volume = {148}, 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 = {1759-7692}, 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{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{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}, } @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{19706, abstract = {The importance of astrocytic l-lactate (LL) for normal functioning of neural circuits such as those regulating learning/memory, sleep/wake state, autonomic homeostasis, or emotional behaviour is being increasingly recognised. l-Lactate can act on neurones as a metabolic or redox substrate, but transmembrane receptor targets are also emerging. A comparative review of the hydroxy-carboxylic acid receptor (HCA1, formerly known as GPR81), Olfactory Receptor Family 51 Subfamily E Member 2 (OR51E2), and orphan receptor GPR4 highlights differences in their LL sensitivity, pharmacology, intracellular coupling, and localisation in the brain. In addition, a putative Gs-coupled receptor on noradrenergic neurones, LLRx, which we previously postulated, remains to be identified. Next-generation sequencing revealed several orphan receptors expressed in locus coeruleus neurones. Screening of a selection of these suggests additional LL-sensitive receptors: GPR180 which inhibits and GPR137 which activates intracellular cyclic AMP signalling in response to LL in a heterologous expression system. To further characterise binding of LL at LLRx, we carried out a structure–activity relationship study which demonstrates that carboxyl and 2-hydroxyl moieties of LL are essential for triggering d-lactate-sensitive noradrenaline release in locus coeruleus, and that the size of the LL binding pocket is limited towards the methyl group position. The evidence accumulating to date suggests that LL acts via multiple receptor targets to modulate distinct brain functions.}, author = {Mosienko, Valentina and Rasooli-Nejad, Seyed and Kishi, Kasumi and De Both, Matt and Jane, David and Huentelman, Matt J. and Kasparov, Sergey and Teschemacher, Anja G.}, issn = {2571-6980}, journal = {Neuroglia}, number = {2}, pages = {365--380}, publisher = {MDPI}, title = {{Putative receptors underpinning L-Lactate signalling in locus coeruleus}}, doi = {10.3390/neuroglia1020025}, volume = {1}, year = {2018}, }