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Organ formation requires integrating signals to coordinate proliferation, specify cell fates, and shape tissue. Tracing these events and signals remains a challenge, as intermediate states across many critical transitions are unresolvable over real time and space. Here, we designed a unique computational approach to decompose a non-linear differentiation process into key components to resolve the signals and cell behaviors that drive a rapid transition, using the hair follicle dermal condensate as a model. Combining scRNA sequencing with genetic perturbation, we reveal that proliferative Dkk1+ progenitors transiently amplify to become quiescent dermal condensate cells by the mere spatiotemporal patterning of Wnt/β-catenin and SHH signaling gradients. Together, they deterministically coordinate a rapid transition from proliferation to quiescence, cell fate specification, and morphogenesis. Moreover, genetically repatterning these gradients reproduces these events autonomously in "slow motion" across more intermediates that resolve the process. This analysis unravels two morphogen gradients that intersect to coordinate events of organogenesis.
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http://dx.doi.org/10.1016/j.devcel.2022.03.011 | DOI Listing |
Semin Cell Dev Biol
September 2025
Division of Biology and Biological Engineering and Department of Physics, California Institute of Technology, Pasadena, CA, USA. Electronic address:
Is a herd of wildebeest better thought of as a series of individual animals, each with its own glorious and unmanageable volition, or as a field of moving arrows? Are the morphogen gradients that set up the coordinate systems for embryonic anterior-posterior patterning a smooth and continuous concentration field or instead a chaotic collection of protein molecules each jiggling about in the haphazard way first described by Robert Brown in his microscopical observations of pollen? Is water, the great liquid ether of the living world, a collection of discrete molecules or instead a perfectly continuous medium with a density of ≈1000 kg/m? In this article, I will argue that these questions pose a false dichotomy since there are many different and powerful representations of the world around us. Different representations suit us differently at different times and it is often useful to be able to hold these seemingly contradictory notions in our heads simultaneously. Indeed, mathematics is not only the language of representation, but often is also the engine of reconciliation of such disparate views.
View Article and Find Full Text PDFDev Cell
August 2025
Francis Crick Institute, London NW11AT, UK. Electronic address:
Morphogen gradients provide the patterning cues that instruct cell fate decisions during development. Here, we establish an optogenetic system for the precise spatiotemporal control in vitro of Sonic hedgehog (Shh) morphogen production. Using a tunable light-inducible gene expression system, we generate long-range Shh gradients that pattern mouse neural progenitors into spatially distinct domains, mimicking neural tube development.
View Article and Find Full Text PDFCell Rep
August 2025
Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA; NSF-Simons National Institute for Theory and Mathematics in Biology, Chicago, IL, USA. Electronic address:
Transcription factors (TFs) regulate gene expression despite constraints from chromatin structure and the cell cycle. Here, we examine the concentration-dependent regulation of hunchback by the Bicoid morphogen through a combination of quantitative imaging, mathematical modeling, and epigenomics in Drosophila embryos. By live imaging of MS2 reporters, we find that, following mitosis, the timing of transcriptional activation driven by the hunchback P2 (hbP2) enhancer directly reflects Bicoid concentration.
View Article and Find Full Text PDFAnnu Rev Genet
August 2025
Max Planck Institute for Biology, Tübingen, Germany; email:
Trained as a biochemist and molecular biologist, in 1975, I began to work on maternal mutants with the aim to isolate morphogens. As group leaders at the European Molecular Biology Laboratory in Heidelberg, Germany, Eric Wieschaus and I discovered 120 genes that control embryonic development. Many of them turned out to be members of important developmental pathways conserved throughout the animal phyla.
View Article and Find Full Text PDFSemin Cell Dev Biol
July 2025
Department of Cell and Developmental Biology, University College London, London, UK. Electronic address:
The field of biological computation has advanced significantly by leveraging natural cellular processes for sophisticated information processing. This review explores how spatially distributed and compartmentalised frameworks for engineered biological computation move beyond traditional single-cell logic systems. By emulating natural phenomena such as morphogen gradients and cellular compartmentalisation, synthetic spatial computing systems have the potential to achieve scalability, robustness, and adaptability.
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