Two DNA technologies map cell development in mouse embryos

Two research teams have used different DNA-recording technologies to trace cell lineages in developing mouse embryos.

Every mammal develops from a single fertilised egg, or zygote, which divides repeatedly to produce all the cells that make up the embryo, its organs and supporting tissue, including the placenta. Tracing cell ancestry can help researchers understand how different cell types emerge, tissues develop and cells become committed to particular fates.

The studies, published in Cell and Science, were described as 'an impressive feat of [genetic] engineering' by Professor Reza Kalhor, a developmental biologist at Johns Hopkins University School of Medicine in Maryland, who was not involved in the research. 'These are the most exciting papers in this field in the last five years, easy,' he added.

Both teams used genome editing to introduce heritable genetic marks into cells as embryos developed. As cells divide, these marks are passed on to their descendants, allowing researchers to reconstruct cells lineages. The teams also used single-cell RNA sequencing to identify cell types and relate lineage history to developmental fate.

One team, led by researchers from the Whitehead Institute at the Massachusetts Institute of Technology in Cambridge and the Max Planck Institute of Molecular Genetics in Germany, used a technique called PEtracer. The method continuously introduces heritable genetic marks as development progresses. Analysing the accumulated marks allows researchers to reconstruct lineage trees and investigate how cell ancestry relates to developmental fate.

The other team, led by researchers at the University of Washington, used a method called DNA Typewriter, a sequential molecular recorder that adds marks to DNA in a specific order, preserving a record of cell divisions over time.

'Think of it like an actual typewriter, except it types onto a cell's own DNA instead of paper,' explained co-first author Dr Haedong Kim. 'Every time a cell divides, it strikes one new character onto the next blank line – always in order, never overwriting what's already there. Because the characters are always filled in sequence, that sequence itself spells out the cell's division history.'

The PEtracer study reconstructed lineage trees across more than 1.4 million cells from 16 mouse embryos, resolving around 75 percent of cell divisions. The DNA Typewriter study reconstructed the lineage history of more than 1.28 million cells from a single embryo at day 13.5 of development. Combining lineage records with gene activity data helped the researchers investigate how cell lineages contribute to different tissues and organs.

Understanding how cells acquire specialised roles could help researchers investigate how developmental processes go awry.

'We are interested in tracking how cells' early ancestry in an embryo influences their later fates. Exploring cell lineages helps decode normal development. Such research could eventually advance knowledge about congenital malformations, neurodevelopmental conditions, genetic disorders or cancer,' said Jay Shendure, professor of genome sciences at the University of Washington and co-corresponding author of the DNA Typewriter paper.

The studies covered different stages of development. The PEtracer study examined mouse embryos between days 7.5 and ten, while the DNA Typewriter study traced cell lineages from the zygote to day 13.5. Neither study followed development through to adulthood. The authors of the DNA Typewriter paper envision that these techniques could one day create a map of life 'from zygote to birth to adulthood to death'.