Biology subjects

Naoki, H.

Publications and source records attributed to Naoki, H..

26 records · Page 2Linked to original sources

bioRxiv2022

Stem cell homeostasis regulated by hierarchy and neutral competition

Tissue stem cells maintain themselves through self-renewal while constantly supplying differentiating cells. As a mechanism of stem cell homeostasis, two distinct models were proposed: the classical model states that there are hierarchy among stem cells and master stem cells provide stem cells by asymmetric divisions, whereas the recent model states that stem cells are equipotent and neutrally competing each other. However, its mechanism is still controversial in several tissues and species. Here, we developed a mathematical model linking these two models. Our theoretical analysis showed that the model with the hierarchy and neutral competition, called the hierarchical neutral competition (hNC) model, exhibited bursts in clonal expansion, unlike existing models. Furthermore, the scaling law in clone size distribution, thought to be a unique characteristic of the recent model, was satisfied in the hNC model. Based on these findings, we proposed a criterion for distinguishing the three models by experiments.

developmental biology↗

bioRxiv2021

Single-cell transcriptome atlas of Drosophila gastrula 2.0

During development, positional information directs cells to specific fates, leading them to differentiate with their own transcriptomes and express specific behaviors and functions. However, the mechanisms underlying these processes in a genome-wide view remain ambiguous, partly because the single-cell transcriptomic data of early developing embryos containing both accurate spatial and lineage information is still lacking. Here, we report a new single-cell transcriptome atlas of Drosophila gastrulae, divided into 65 transcriptomically distinct clusters. We found that the expression profiles of plasma-membrane-related genes, but not those of transcription factor genes, represented each germ layer, supporting the nonequivalent contribution of each transcription factor mRNA level to effector gene expression profiles at the transcriptome level. We also reconstructed the spatial expression patterns of all genes at the single-cell stripe level as the smallest unit. This atlas is an important resource for the genome-wide understanding of the mechanisms by which genes cooperatively orchestrate Drosophila gastrulation.

developmental biology↗

bioRxiv2020

Model-based prediction of spatial gene expression via generative linear mapping

Decoding spatial transcriptomes from single-cell RNA sequencing (scRNA-seq) data has become a fundamental technique for understanding multicellular systems; however, existing computational methods lack both accuracy and biological interpretability due to their model-free frameworks. Here, we introduced Perler, a model-based method to integrate scRNA-seq data with reference in situ hybridization (ISH) data. To calibrate differences between these datasets, we developed a biologically interpretable model that uses generative linear mapping based on a Gaussian-mixture model using the Expectation-Maximization algorithm. Perler accurately predicted the spatial gene expression of Drosophila embryos, zebrafish embryos, mammalian liver, and mouse visual cortex from scRNA-seq data. Furthermore, the reconstructed transcriptomes did not over-fit the ISH data and preserved the timing information of the scRNA-seq data. These results demonstrated the generalizability of Perler for dataset integration, thereby providing a biologically interpretable framework for accurate reconstruction of spatial transcriptomes in any multicellular system.

genomics↗

bioRxiv2019

Hierarchical modeling of mechano-chemical dynamics of epithelial sheets across cells and tissue

Collective cell migration is a macroscopic population-level phenomenon that has emerged across hierarchy from mi-croscopic interactions between cells; however, the underlying mechanism remains unclear. Here, we targeted epithe-lial collective cell migration, driven by the mechanical force regulated by chemical signals of traveling ERK activation waves, observed in wound healing. We propose a hierarchical mathematical framework for understanding how cells are orchestrated through mechanochemical cell-cell interaction. We mathematically transformed a particle-based model at the cellular level into a continuum model at the tissue level. The continuum model described relationships between cell migration and mechanochemical variables, namely, ERK activity gradients, cell density, and velocity field, which could be compared with live-cell imaging data. The continuum model recapitulated the ERK wave-induced collective cell migration in wound healing. We also numerically confirmed a consistency between the two models. This framework allows us to connect hierarchical causality from the single-cell level to the tissue level.

biophysics↗

bioRxiv2018

Noise-resistant developmental reproducibility in vertebrate somite formation

The reproducibility of embryonic development is remarkable, although molecular processes are intrinsically stochastic at the single-cell level. How the multi-cellular system resists the inevitable noise to acquire developmental reproducibility constitutes a fundamental question in developmental biology. Toward this end, we focused on vertebrate somitogenesis as a representative system, because somites are repeatedly reproduced within a single embryo whereas such reproducibility is lost in segmentation clock gene-deficient embryos. However, the effect of noise on developmental reproducibility has not been fully investigated, because of the technical difficulty in manipulating the noise intensity in experiments. In this study, we developed a computational model of ERK-mediated somitogenesis, in which bistable ERK activity is regulated by an FGF gradient, cell-cell communication, and the segmentation clock, subject to the intrinsic noise. The model simulation generated our previous in vivo observation that the ERK activity was distributed in a step-like gradient in the presomitic mesoderm, and its boundary was posteriorly shifted by the clock in a stepwise manner, leading to regular somite formation. Here we showed that this somite regularity was robustly maintained against the noise. Removing the clock from the model predicted that the stepwise shift of the ERK activity occurs at irregular timing with irregular distance owing to the noise, resulting in somite size variation. Through theoretical analysis, we presented a mechanism by which the clock reduces the inherent somite irregularity observed in clock-deficient embryos. Therefore, this study indicates a novel role of the segmentation clock in noise-resistant developmental reproducibility.

developmental biology↗

bioRxiv2017

Self-organization mechanism of distinct microtubule orientations in axons and dendrites

The identities of axons and dendrites are acquired through the self-organization of distinct microtubule (MT) orientations during neuronal polarization. The axon is generally characterized by a uniform MT orientation with all plus-ends pointing outward to the neurite terminal ( plus-end-out pattern). On the other hand, the MT orientation pattern in the dendrites depends on species: vertebrate dendrites have a mixed alignment with both plus and minus ends facing either the terminal or the cell body ( mixed pattern), whereas invertebrate dendrites have a minus-end-out pattern. However, how MT organizations are developed in the axon and the dendrites is largely unknown. To investigate the mechanism of MT organization, we developed a biophysical model of MT kinetics, consisting of polymerization/depolymerization and MT catastrophe coupled with neurite outgrowth. The model simulation showed that the MT orientation can be controlled mainly by the speed of neurite growth and the hydrolysis rate. With a low hydrolysis rate, vertebrate plus-end-out and mixed microtubule patterns emerged in fast- and slow-growing neurites, respectively. In contrast, with a high hydrolysis rate, invertebrate plus-end-out and minus-end-out microtubule patterns emerged in fast- and slow-growing neurites, respectively. Thus, our model can provide a unified understanding of distinct microtubule organizations by simply changing the parameters.

neuroscience↗

bioRxiv2017

Revisiting Chemoaffinity Theory: Chemotactic Implementation Of Topographic Axonal Projection

Neural circuits are wired by chemotactic migration of growth cones guided by extracellular guidance cue gradients. How growth cone chemotaxis builds the macroscopic structure of the neural circuit is a fundamental question in neuroscience. I addressed this issue in the case of the ordered axonal projections called topographic maps in the retinotectal system. In the retina and tectum, the erythropoietin-producing hepatocellular (Eph) receptors and their ligands, the ephrins, are expressed in gradients. According to Sperrys chemoaffinity theory, gradients in both the source and target areas enable projecting axons to recognize their proper terminals, but how axons chemotactically decode their destinations is largely unknown. To identify the chemotactic mechanism of topographic mapping, I developed a mathematical model of intracellular signaling in the growth cone that focuses on the growth cones unique chemotactic property of being attracted or repelled by the same guidance cues in different biological situations. The model presented mechanism by which the retinal growth cone reaches the correct terminal zone in the tectum through alternating chemotactic response between attraction and repulsion around a preferred concentration. The model also provided a unified understanding of the contrasting relationships between receptor expression levels and preferred ligand concentrations in EphA/ephrinA- and EphB/ephrinB-encoded topographic mappings. Thus, this study redefines the chemoaffinity theory in chemotactic terms.\n\nAuthor SummaryThis study revisited the chemoaffinity theory for topographic mapping in terms of chemotaxis. According to this theory, the axonal growth cone projects to specific targets based on positional information encoded by chemical gradients in both source and target areas. However, the mechanism by which the chemotactic growth cone recognizes its proper terminal site remains elusive. To unravel this mystery, I mathematically modeled a growth cone exhibiting concentration-dependent attraction and repulsion to chemotactic cues. The model identified a novel growth cone guidance mechanism in topographic mapping, highlighting the importance of the growth cones unique ability to alternate between attraction and repulsion. Furthermore, an extension of the model provided possible molecular mechanisms for contrasting two types of topographic mappings observed in the retinotectal system.

neuroscience↗

bioRxiv2017

Identification Of Animal Behavioral Strategy By Inverse Reinforcement Learning ~ Its Application To Thermotaxis In C. elegans ~

Animals are able to reach a desired state in an environment by controlling various behavioral patterns. Identification of the behavioral strategy used for this control is important for understanding animals decision-making and is fundamental to dissect information processing done by the nervous system. However, methods for quantifying such behavioral strategies have not been fully established. In this study, we developed an inverse reinforcement-learning (IRL) framework to identify an animals behavioral strategy from behavioral time-series data. As a particular target, we applied this framework to C. elegans thermotactic behavior; after cultivation at a constant temperature with or without food, the fed and starved worms prefer and avoid from the cultivation temperature on a thermal gradient, respectively. Our IRL approach revealed that the fed worms used both absolute and temporal derivative of temperature and that their strategy comprised mixture of two strategies: directed migration (DM) and isothermal migration (IM). The DM is a strategy that the worms efficiently reach to specific temperature, which explained thermotactic behaviors of the fed worms. The IM is a strategy that the worms track along a constant temperature, which reflects isothermal tracking well observed in previous studies. We also showed the neural basis underlying the strategies, by applying our method to thermosensory neuron-deficient worms. In contrast to fed animals, the strategy of starved animals indicated that they escaped the cultivation temperature using only absolute, but not temporal derivative of temperature. Thus, our IRL-based approach is capable of identifying animal strategies from behavioral time-series data and will be applicable to wide range of behavioral studies, including decision-making of other organisms.\n\nAuthor SummaryUnderstanding animal decision-making has been a fundamental problem in neuroscience and behavioral ecology. Many studies analyze actions that represent decision-making in behavioral tasks, in which rewards are artificially designed with specific objectives. However, it is impossible to extend this artificially designed experiment to a natural environment, because in a natural environment, the rewards for freely-behaving animals cannot be clearly defined. To this end, we must reverse the current paradigm so that rewards are identified from behavioral data. Here, we propose a new reverse-engineering approach (inverse reinforcement learning) that can estimate a behavioral strategy from time-series data of freely-behaving animals. By applying this technique with thermotaxis in C. elegans, we successfully identified the reward-based behavioral strategy.

neuroscience↗