Temporal and Spatial Coordination of Development

The remarkable diversity of neuronal and glial subtypes produced in the neural tube depends on a combination of spatial and temporal patterning. Coordinating these processes is crucial yet underexplored. Our research has revealed that spatially distinct progenitor domains generate molecularly different types of neurons and glia in a specific sequential order. This intersection of spatial and temporal identity not only increases molecular diversity but also organizes the arrangement of functionally distinct cell types.

We’ve identified a global temporal programme operating in progenitors throughout the vertebrate nervous system. This governs cell fate choices by regulating chromatin accessibility, a finding that emphasises the importance of understanding how developmental tempo is controlled at the molecular level. Perturbation of this cis-regulatory program affects sequential cell fate transitions in neural progenitors and the identity of their progeny, highlighting its critical role in developmental progression. This chronotopic spatiotemporal integration strategy, where a global temporal chromatin programme determines the output of the spatial gene regulatory network, results in the temporally and spatially ordered allocation of cell type identity. Understanding how this temporal programme controls the chromatin landscape of progenitors to determine their temporal identity is a focus of our research.

While the molecular and cellular mechanisms of neural tube development are evolutionarily conserved among vertebrates, the pace at which these operate varies considerably between species. For instance, motor neuron differentiation takes two to three times longer in human than mouse. This variation in developmental tempo presents a fascinating area of investigation. Our research, taking advantage of access to human embryos and in vitro stem cell models, has revealed a correlation between protein stability and developmental tempo. We found that slower temporal progression in humans corresponded to increased protein stability, suggesting a potential explanation for the substantial variation in developmental pace between species. These findings open up new avenues for exploring how species-specific rates of protein turnover are controlled and how they influence the overall tempo of development.

Concurrent with patterning, the neural tube grows over time as progenitors proliferate. The coordination of cell proliferation, movement, and neuronal differentiation with patterning is a complex process that we are actively investigating. We aim to understand how growth and patterning of the neural tube at the population level emerge from the collective behaviours of individual cells. To achieve the necessary single-cell resolution, we are employing clonal lineage tracing methods. These data allow us to determine the rates and probabilities of cell division and to identify any anisotropic growth produced by biases in division orientation or cell movement.

By integrating these parameters into mathematical models that describe neural tube growth, we aim to make experimental predictions to test and refine our understanding of how growth and patterning are coordinated at the molecular level. This approach not only sheds light on the fundamental principles governing neural development but also provides insights into how the tempo of development is regulated and maintained across different scales, from molecular interactions to tissue-level organization.

By elucidating the mechanisms that control the pace and timing of developmental events, we are gaining a more comprehensive understanding of nervous system formation. This knowledge has implications for our basic understanding of developmental biology and potentially informs regenerative medicine strategies as well

SELECTED PUBLICATIONS

Isabel Zhang, Giulia LM Boezio, Jake Cornwall-Scoones, Thomas Frith, Ming Jiang, Michael Howell, Robin Lovell-Badge, Andreas Sagner, James Briscoe, M Joaquina Delás (2024)
The cis-regulatory logic integrating spatial and temporal patterning in the vertebrate neural tube
bioRxiv 2024.04.17.589864

Rayon T, Stamataki D, Perez-Carrasco R, Garcia-Perez L, Barrington C, Melchionda M, Exelby K, Lazaro J, Tybulewicz VLJ, Fisher EMC, Briscoe J (2020)
Species-specific pace of development is associated with differences in protein stability.
Science 369(6510):eaba7667

Sagner A, Zhang I, Watson T, Lazaro J, Melchionda M, Briscoe J. (2021)
A shared transcriptional code orchestrates temporal patterning of the central nervous system
PLoS Biology 19:e3001450

Guerrero P, Perez-Carrasco R, Zagorski M, Page D, Kicheva A, Briscoe J, Page KM. (2019)
Neuronal differentiation influences progenitor arrangement in the vertebrate neuroepithelium.
Development. 146:dev176297 32450962