Researchers have mapped the relationships between the cells of a mouse embryo, tracing their lineages from the first cell division until the body and its organs had formed. This developmental period lasted 13.5 days. A full mouse pregnancy typically lasts about 19 to 21 days. The findings were published in the journal Science.
Dr. Jay Shendure led the research alongside Dr. Chengxiang Qiu. Shendure is a genome scientist at the University of Washington School of Medicine in Seattle and an investigator at the Howard Hughes Medical
Institute. Qiu is affiliated with Dartmouth College in New Hampshire.
Shendure explained that the team aims to understand how a cell’s early ancestors influence whaDNA Typewritert it eventually becomes. Studying these cellular family trees can help scientists understand normal development. In the future, this knowledge may also provide insights into birth defects, neurodevelopmental disorders, inherited diseases, and cancer.
The team used a tool called DNA Typewriter, developed by Shendure and Junhong Choi of Memorial Sloan Kettering Cancer Center. For this study, the researchers inserted a newly improved recording sequence into a fertilized mouse egg. The sequence uses the mouse’s own DNA to store information about the cell’s history.
The redesigned system makes these records easier to retrieve and interpret from individual cells. As the embryo develops, the recording sequence remains inside its cells, functioning much like a ship’s logbook.
Haedong Kim, a co-first author and postdoctoral researcher at UW Medicine, compared the technology to a conventional typewriter. However, instead of typing on paper, DNA Typewriter records information in a cell’s DNA. Each time a cell divides, a new character is added to the next available position in the sequence. Earlier characters are never overwritten. Because the characters are recorded in a fixed order, the resulting sequence reveals the cell’s division history.
Daughter cells inherit these records from their parent cells. When cells share the same markings, researchers can determine that they descended from a common ancestor. Kim explained that recording the information is only half the challenge; retrieving and interpreting it from individual cells is equally difficult. This was one of the main reasons the team redesigned the recording sequence.
Tracing cell lineages in mammals is particularly challenging because a mouse’s body contains enormous numbers of cells representing many different cell types. Decades ago, researchers successfully traced the lineage of every cell in a tiny roundworm. The worm’s transparent body and relatively simple structure, with its limited number of cells, made the task considerably easier. Earlier attempts to map cell lineages in mice produced valuable findings, but the resulting pictures remained incomplete.
Previous methods also had several limitations. They often involved cutting DNA, which could leave molecular scars and place stress on cells. These techniques could erase earlier records and quickly exhaust the available recording space. Furthermore, their markers were not added in a fixed sequence, forcing scientists to reconstruct the timeline and infer the order of cellular events afterward.
According to Kim, DNA Typewriter overcomes several of these limitations. It records information without extensively cutting the DNA, maintains a relatively steady recording pace, and adds markers in a strict sequence. These features allow researchers to reconstruct cell lineages in greater detail and over a longer developmental period.
The team tested the recording system in 100 fertilized mouse eggs and ultimately obtained 10 embryos for analysis. Among them, Embryo No. 3 showed clear recording activity and contained the richest developmental history. The researchers therefore concentrated their detailed analysis on this embryo.
The study produced several important insights. First, the recording system captured a clear, persistent marker distinguishing the two cells formed during the first division of the fertilized egg. This enabled the researchers to trace almost every profiled cell back to one of these two founding cells. Although one founding cell produced more descendants than the other, both contributed to a wide range of cell types in nearly equal proportions.
Second, the researchers were able to pinpoint when different cell types first diverged onto their own developmental paths. Blood cells and retinal cells began differentiating relatively early, whereas the outer layer of the skin committed to its distinct developmental pathway much later.
