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1. Early radial positional information in the cochlea is optimized by a precise linear BMP gradient and enhanced by SOX2

   https://doi.org/10.1038/s41598-023-34725-4  

   Thompson, Matthew J.; Young, Caryl A.; Munnamalai, Vidhya; Umulis, David M. (December 2023, Scientific Reports)

   Abstract Positional information encoded in signaling molecules is essential for early patterning in the prosensory domain of the developing cochlea. The sensory epithelium, the organ of Corti, contains an exquisite repeating pattern of hair cells and supporting cells. This requires precision in the morphogen signals that set the initial radial compartment boundaries, but this has not been investigated. To measure gradient formation and morphogenetic precision in developing cochlea, we developed a quantitative image analysis procedure measuring SOX2 and pSMAD1/5/9 profiles in mouse embryos at embryonic day (E)12.5, E13.5, and E14.5. Intriguingly, we found that the pSMAD1/5/9 profile forms a linear gradient up to the medial ~ 75% of the PSD from the pSMAD1/5/9 peak in the lateral edge during E12.5 and E13.5. This is a surprising activity readout for a diffusive BMP4 ligand secreted from a tightly constrained lateral region since morphogens typically form exponential or power-law gradient shapes. This is meaningful for gradient interpretation because while linear profiles offer the theoretically highest information content and distributed precision for patterning, a linear morphogen gradient has not yet been observed. Furthermore, this is unique to the cochlear epithelium as the pSMAD1/5/9 gradient is exponential in the surrounding mesenchyme. In addition to the information-optimized linear profile, we found that while pSMAD1/5/9 is stable during this timeframe, an accompanying gradient of SOX2 shifts dynamically. Last, through joint decoding maps of pSMAD1/5/9 and SOX2, we see that there is a high-fidelity mapping between signaling activity and position in the regions that will become Kölliker’s organ and the organ of Corti. Mapping is ambiguous in the prosensory domain precursory to the outer sulcus. Altogether, this research provides new insights into the precision of early morphogenetic patterning cues in the radial cochlea prosensory domain. 

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2. A multiscale chemical-mechanical model predicts impact of morphogen spreading on tissue growth

   https://doi.org/10.1038/s41540-023-00278-5  

   Ramezani, Alireza; Britton, Samuel; Zandi, Roya; Alber, Mark; Nematbakhsh, Ali; Chen, Weitao (May 2023, npj Systems Biology and Applications)

   Abstract The exact mechanism controlling cell growth remains a grand challenge in developmental biology and regenerative medicine. The Drosophila wing disc tissue serves as an ideal biological model to study mechanisms involved in growth regulation. Most existing computational models for studying tissue growth focus specifically on either chemical signals or mechanical forces. Here we developed a multiscale chemical-mechanical model to investigate the growth regulation mechanism based on the dynamics of a morphogen gradient. By comparing the spatial distribution of dividing cells and the overall tissue shape obtained in model simulations with experimental data of the wing disc, it is shown that the size of the domain of the Dpp morphogen is critical in determining tissue size and shape. A larger tissue size with a faster growth rate and more symmetric shape can be achieved if the Dpp gradient spreads in a larger domain. Together with Dpp absorbance at the peripheral zone, the feedback regulation that downregulates Dpp receptors on the cell membrane allows for further spreading of the morphogen away from its source region, resulting in prolonged tissue growth at a more spatially homogeneous growth rate. 

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3. Determining the role of advection in patterning by bone morphogenetic proteins through neural network model-based acceleration of a 3D finite element model of the zebrafish embryo

   https://doi.org/10.3389/fsysb.2022.983372  

   Li, Linlin; Wang, Xu; Chai, Junyi; Wang, Xiaoqian; Buganza-Tepole, Adrian; Umulis, David M. (October 2022, Frontiers in Systems Biology)

   Embryonic development is a complex phenomenon that integrates genetic regulation and biomechanical cellular behaviors. However, the relative influence of these factors on spatiotemporal morphogen distributions is not well understood. Bone Morphogenetic Proteins (BMPs) are the primary morphogens guiding the dorsal-ventral (DV) patterning of the early zebrafish embryo, and BMP signaling is regulated by a network of extracellular and intracellular factors that impact the range and signaling of BMP ligands. Recent advances in understanding the mechanism of pattern formation support a source-sink mechanism, however, it is not clear how the source-sink mechanism shapes the morphogen patterns in three-dimensional (3D) space, nor how sensitive the pattern is to biophysical rates and boundary conditions along both the anteroposterior (AP) and DV axes of the embryo, nor how the patterns are controlled over time. Throughout blastulation and gastrulation, major cell movement, known as epiboly, happens along with the BMP-mediated DV patterning. The layer of epithelial cells begins to thin as they spread toward the vegetal pole of the embryo until it has completely engulfed the yolk cell. This dynamic domain may influence the distributions of BMP network members through advection. We developed a Finite Element Model (FEM) that incorporates all stages of zebrafish embryonic development data and solves the advection-diffusion-reaction Partial Differential Equations (PDE) in a growing domain. We use the model to investigate mechanisms in underlying BMP-driven DV patterning during epiboly. Solving the PDE is computationally expensive for parameter exploration. To overcome this obstacle, we developed a Neural Network (NN) metamodel of the 3D embryo that is accurate and fast and provided a nonlinear map between high-dimensional input and output that replaces the direct numerical simulation of the PDEs. From the modeling and acceleration by the NN metamodels, we identified the impact of advection on patterning and the influence of the dynamic expression level of regulators on the BMP signaling network. 

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4. Bicoid-nucleosome competition sets a concentration threshold for transcription constrained by genome replication

   https://doi.org/10.1101/2024.12.10.627802  

   Degen, Eleanor A; Croslyn, Corinne; Mangan, Niall M; Blythe, Shelby A (December 2024, bioRxiv)

   SUMMARY Transcription factors (TFs) regulate gene expression despite constraints from chromatin structure and the cell cycle. Here we examine the concentration-dependent regulation ofhunchbackby the Bicoid morphogen through a combination of quantitative imaging, mathematical modeling and epigenomics inDrosophilaembryos. By live imaging of MS2 reporters, we find that, following mitosis, the timing of transcriptional activation driven by thehunchbackP2 (hbP2) enhancer directly reflects Bicoid concentration. We build a stochastic model that can explainin vivoonset time distributions by accounting for both the competition between Bicoid and nucleosomes athbP2 and a negative influence of DNA replication on transcriptional elongation. Experimental modulation of nucleosome stability alters onset time distributions and the posterior boundary ofhunchbackexpression. We conclude that TF-nucleosome competition is the molecular mechanism whereby the Bicoid morphogen gradient specifies the posterior boundary ofhunchbackexpression. 

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5. Intracellular protein gradients serve a variety of functions, such as the establishment of cell polarity or to provide positional information for gene expression in developing embryos. Given that cell size in a population can vary considerably, for the protein gradients to work properly they often have to be scaled to the size of the cell. Here, we examine a model of protein gradient formation within a cell that relies on cytoplasmic diffusion and cortical transport of proteins toward a cell pole. We show that the shape of the protein gradient is determined solely by the cell geometry. Furthermore, we show that the length scale over which the protein concentration in the gradient varies is determined by the linear dimensions of the cell, independent of the diffusion constant or the transport speed. This gradient provides scale-invariant positional information within a cell, which can be used for assembly of intracellular structures whose size is scaled to the linear dimensions of the cell, such as the cytokinetic ring and actin cables in budding yeast cells.

   https://doi.org/10.7554/eLife.71365  

   Datta, Arnab; Ghosh, Sagnik; Kondev, Jane (March 2022, eLife)

   Intracellular protein gradients serve a variety of functions, such as the establishment of cell polarity or to provide positional information for gene expression in developing embryos. Given that cell size in a population can vary considerably, for the protein gradients to work properly they often have to be scaled to the size of the cell. Here, we examine a model of protein gradient formation within a cell that relies on cytoplasmic diffusion and cortical transport of proteins toward a cell pole. We show that the shape of the protein gradient is determined solely by the cell geometry. Furthermore, we show that the length scale over which the protein concentration in the gradient varies is determined by the linear dimensions of the cell, independent of the diffusion constant or the transport speed. This gradient provides scale-invariant positional information within a cell, which can be used for assembly of intracellular structures whose size is scaled to the linear dimensions of the cell, such as the cytokinetic ring and actin cables in budding yeast cells. 

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