Timothy Fulton

University of Cambridge

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Benjamin Steventon

University of Cambridge

Leila Mureşan

University of Cambridge

Andrea Attardi

University of Palermo

Courtney Lancaster

University College London

Berta Verd

University of Oxford

Kay Spiess

The Alan Turing Institute

Yuxuan Wang

Boston University

Alexander van Oudenaarden

University Medical Center Utrecht

Maria Florescu

University Medical Center Utrecht

Jan Huisken

University of Göttingen

Cooperative Institutions

University of Cambridge

Somerville Hospital

International Rice Research Institute

University of Sheffield

University of Oxford

University of Nottingham

European Molecular Biology Laboratory

Goethe University Frankfurt

University of North Carolina at Chapel Hill

University College London

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Neuromesodermal progenitors are a conserved source of spinal cord with divergent growth dynamics

Development (2018)

Andrea Attardi Timothy Fulton Maria Florescu Gopi Shah Leila Mureşan

During gastrulation, embryonic cells become specified into distinct germ layers. In mouse, this continues throughout somitogenesis from a population of bipotent stem cells called neuromesodermal progenitors (NMps). However, the degree of self-renewal associated with NMps in the fast-developing zebrafish embryo is unclear. Using a genetic clone-tracing method, we labelled early embryonic progenitors and found a strong clonal similarity between spinal cord and mesoderm tissues. We followed individual cell lineages using light-sheet imaging, revealing a common neuromesodermal lineage contribution to a subset of spinal cord tissue across the anterior-posterior body axis. An initial population subdivides at mid-gastrula stages and is directly allocated to neural and mesodermal compartments during gastrulation. A second population in the tailbud undergoes delayed allocation to contribute to the neural and mesodermal compartment only at late somitogenesis. Cell tracking and retrospective cell fate assignment at late somitogenesis stages reveal these cells to be a collection of mono-fated progenitors. Our results suggest that NMps are a conserved population of bipotential progenitors, the lineage of which varies in a species-specific manner due to vastly different rates of differentiation and growth.

Somitogenesis

Germ layer

Progenitor

10.1242/dev.166728

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Citations (71)

From in silico to in Vitro to In Vivo: Increasing Megakaryocytes to Treat Thrombocytopenia

Blood (2023)

Alejandra Macias Mauricio Cortes Na An Na Li Timothy Fulton

Transferrin receptor

10.1182/blood-2023-190250

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Axis Specification in Zebrafish Is Robust to Cell Mixing and Reveals a Regulation of Pattern Formation by Morphogenesis

Current Biology (2020)

Timothy Fulton Vikas Trivedi Andrea Attardi Kerim Anlaş Chaitanya Dingare

A fundamental question in developmental biology is how the early embryo establishes the spatial coordinate system that is later important for the organization of the embryonic body plan. Although we know a lot about the signaling and gene-regulatory networks required for this process, much less is understood about how these can operate to pattern tissues in the context of the extensive cell movements that drive gastrulation. In zebrafish, germ layer specification depends on the inheritance of maternal mRNAs [1-3], cortical rotation to generate a dorsal pole of β-catenin activity [4-8], and the release of Nodal signals from the yolk syncytial layer (YSL) [9-12]. To determine whether germ layer specification is robust to altered cell-to-cell positioning, we separated embryonic cells from the yolk and allowed them to develop as spherical aggregates. These aggregates break symmetry autonomously to form elongated structures with an anterior-posterior pattern. Both forced reaggregation and endogenous cell mixing reveals how robust early axis specification is to spatial disruption of maternal pre-patterning. During these movements, a pole of Nodal signaling emerges that is required for explant elongation via the planar cell polarity (PCP) pathway. Blocking of PCP-dependent elongation disrupts the shaping of opposing poles of BMP and Wnt/TCF activity and the anterior-posterior patterning of neural tissue. These results lead us to suggest that embryo elongation plays a causal role in timing the exposure of cells to changes in BMP and Wnt signal activity during zebrafish gastrulation. VIDEO ABSTRACT.

10.1016/j.cub.2020.05.048

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Citations (55)

Correction: Neuromesodermal progenitors are a conserved source of spinal cord with divergent growth dynamics

Development (2020)

Andrea Attardi Timothy Fulton Maria Florescu Gopi Shah Leila Mureşan

There was an error in Development (2018) 145, [dev166728][1] ([doi:10.1242/dev.166728][2]). In [Fig. 6][3], the graph in panel G was duplicated in panel I. Corrected: ![Fig. 6.][4] Fig. 6. Quantification of cell division in tailbud NMps. Quantification of increase in number of cells

Dynamics

10.1242/dev.195610

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Citations (1)

Effects of ethanol on HDAC mRNA and protein expression.

Yuan Jian Timothy Fulton

10.1371/journal.pone.0087915.g006

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Approximated Gene Expression Trajectories (AGETs) for Gene Regulatory Network Inference on Cell Tracks

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Kay Spiess Shannon E. Taylor Timothy Fulton Kane Toh Dillan Saunders

Abstract The study of pattern formation has greatly benefited from our ability to reverse-engineer gene regulatory network (GRN) structure from spatio-temporal quantitative gene expression data. Traditional approaches omit tissue morphogenesis, and focus on systems where the timescales of pattern formation and morphogenesis can be separated. In such systems, pattern forms as an emergent property of the underlying GRN and mechanistic insight can be obtained from the GRNs alone. However, this is not the case in most animal patterning systems, where patterning and morphogenesis are co-occurring and tightly linked. To address the mechanisms driving pattern formation in such systems we need to adapt our GRN inference methodologies to explicitly accommodate cell movements and tissue shape changes. In this work we present a novel framework to reverse-engineer GRNs underlying pattern formation in tissues undergoing morphogenetic changes and cell rearrangements. By integrating quantitative data from live and fixed embryos, we approximate gene expression trajectories (AGETs) in single cells and use a subset to reverse-engineer candidate GRNs using a Markov Chain Monte Carlo approach. GRN fit is assessed by simulating on cell tracks (live-modelling) and comparing the output to quantitative data-sets. This framework generates candidate GRNs that recapitulate pattern formation at the level of the tissue and the single cell. To our knowledge, this inference methodology is the first to integrate cell movements and gene expression data, making it possible to reverse-engineer GRNs patterning tissues undergoing morphogenetic changes.

Gene regulatory network

Expression (computer science)

10.1101/2022.01.12.476060

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Long-term in toto cell tracking using lightsheet microscopy of the zebrafish tailbud

Wellcome Open Research (2019)

Timothy Fulton Martin O. Lenz Leila Mureşan Toby G. R. Andrews Courtney Lancaster

In toto light-sheet imaging allows the tracking of entire growing tissues with high spatial and temporal resolution for many hours. However, this technology requires a sample to be immobilised to ensure that the tissue of interest remains within the field of view throughout the image acquisition period. We have developed a method of mounting and image capture for long-term light-sheet imaging of a growing zebrafish tailbud from the 18 somite stage through to the end of somitogenesis. By tracking the global movement of the tailbud during image acquisition and feeding this back to the microscope stage, we are able to ensure that the growing tissue remains within the field of view throughout image acquisition. Here, we present three representative datasets of embryos in which all nuclei are labelled and tracked until the completion of somitogenesis.

Somitogenesis

Tracking (education)

10.12688/wellcomeopenres.14907.2

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Neurodegeneration and Regeneration During Alcohol Dependence and Recovery are regulated by Liver and Brain Cytokines

Nihon Arukōru, Yakubutsu Igakkai zasshi (2008)

Timothy Fulton

Liver Regeneration

Source

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Negative feedback on Retinoic Acid by Brachyury guides gastruloid symmetry-breaking

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Meagan J. Hennessy Timothy Fulton David A. Turner Benjamin Steventon

Abstract Establishment of the vertebrate body plan requires a combination of extra-embryonic signalling to establish morphogen gradients, and an underlying self-assembly mechanism that contributes to pattern regulation and robustness. Gastruloids are aggregates of mouse embryonic stem cells that break morphological symmetry and polarise Brachyury ( Bra ) expression in the absence of extra-embryonic signals. However, the mechanism by which symmetry breaking occurs is not yet known. During gastrulation and body axis elongation, retinoic acid (RA) and Cyp26a1 are polarised along the anteroposterior axis, and this is critical for balancing the decision of cells to self-renew or differentiate. We found that symmetry-breaking in gastruloids is coincident with the separation of Aldh1a2 and Cyp26a1 expression, and that feedback from Bra is critical for maintaining polarised Cyp26a1 gene expression in the gastruloid posterior region. Furthermore, we reveal a short temporal window where RA signalling can negatively influence both Bra and Cyp26a1 expression. These observations lead us to suggest a mechanism of how initial gastruloid patterning, subsequent elongation, and evolving network topologies can create defined boundaries of RA signalling that permits proper axial patterning and gastruloid growth.

Brachyury

Morphogen

10.1101/2023.06.02.543388

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Citations (8)

Long-term in toto cell tracking using lightsheet microscopy of the zebrafish tailbud

Wellcome Open Research (2018)

Timothy Fulton Martin O. Lenz Leila Mureşan Courtney Lancaster Elizabeth Horton

Somitogenesis

Tracking (education)

10.12688/wellcomeopenres.14907.1

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