For decades, scientists have examined individual stages of embryonic development through snapshots of a developing brain, images showing how the heart takes shape and observations of cells beginning to form the nervous system. The new research moves beyond these isolated observations by reconstructing how development unfolds over time.
The study was conducted by a team led by MIT Professor Jonathan Weissman, a member of the Whitehead Institute for Biomedical Research and an investigator at the Howard Hughes Medical Institute. Published as an open-access paper in the journal Cell on October 8, the research was carried out in collaboration with Zachary Smith's group at Yale University and the Max Planck Institute for Molecular Genetics.
The researchers created a developmental blueprint that follows the histories of individual cells, showing how they divide and contribute to the tissues and organs of a developing mouse. The work offers a comprehensive view of a process that has traditionally been studied in separate stages: how a single fertilized egg produces hundreds of different cell types, which must be arranged in the correct locations and at the right times to build an animal.
"This is really a view of how the information in the genome plays out over space and time to go from linear DNA to a three-dimensional animal," Weissman said.
The map could have significant implications for research into birth defects and cancer. Many birth defects arise when cells change their developmental paths while tissues and organs are being assembled. A detailed record of normal development could help researchers identify when and where these processes go wrong.
In cancer research, the same approach could help scientists trace when cells acquire characteristics such as the ability to spread or resist treatment. The findings could also inform stem cell research by revealing the sequence of cellular states through which cells progress before becoming mature, functional cell types.
Scientists have previously attempted to reconstruct developmental processes at the cellular level. In the 1980s, researchers painstakingly tracked the development of Caenorhabditis elegans, a tiny worm with a transparent body containing only about 1,000 cells. Using microscopy, they followed individual cell divisions and traced where the resulting cells ended up.
Applying a similar approach to mammals presents a much greater challenge. Mammalian embryos contain far more cells, develop inside the uterus and remain out of sight during development. Their development also does not follow a completely predetermined script.
To overcome these obstacles, the MIT-led team used PEtracer, a technology developed in the Weissman Lab. The system works like a flight recorder inside a cell, introducing small, heritable changes into DNA that are passed on as cells divide.
By reading these changes later, scientists can reconstruct the relationships between cells and identify their ancestors. This allows them to build a family tree of cells within a developing embryo and trace how different cell populations emerge.
For the study, the researchers combined these cellular family trees with information about which genes were active in individual cells and where those cells were located within the embryo. They analysed more than a million cells collected from mouse embryos at multiple points during development.
Sampling embryos at different stages enabled the team to determine not only where cells eventually ended up, but also when they began moving towards particular developmental fates.
A separate study from Jay Shendure's group at the University of Washington, published concurrently in the journal Science, used a related technology called DNA Typewriter to track cell divisions in developing mouse embryos and create a record of their cellular histories.
Both studies provide a more comprehensive view of mammalian development than was previously available. However, the Weissman team examined embryos at closely spaced developmental stages and analysed multiple embryos at each stage. This approach provided a more detailed timeline of development and allowed the researchers to investigate how consistently cells followed the same developmental paths across different embryos.
Using this timeline, the researchers could also determine when cells committed to particular developmental fates, how many early cells contributed to the formation of a tissue and how those cells ultimately participated in building a developing organ.
By connecting cellular ancestry with gene activity, location and developmental timing, the research establishes a detailed framework for understanding how a fertilized egg develops into a complex mammal. The findings could help scientists investigate the origins of developmental abnormalities, trace the emergence of cancer-related traits and better understand the pathways that lead stem cells to become mature, functional cells.
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