@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{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{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}, } @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{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}, }