Researchers at Karolinska Institutet have developed a method that makes it possible to track how different cell types in the gut form during fetal development in mice. The method provides new insights into how the tissues and nervous system of the gut develop and can also be used to investigate how genes influence these processes. The results are published in the journal PNAS.
The gut consists of many different types of cells that need to end up in the right place and acquire the right function during fetal development. Studying how this happens has been difficult, partly because methods for labelling and tracking cells in the growing gut have been lacking.
In the current study, the researchers developed a method in which genetic "barcodes" are introduced into early mouse embryos through so-called in utero injection. The barcodes are passed on as the cells divide, making it possible to map which cell types share a common origin.
By tracking the barcoded cells, the researchers found that different parts of the gut develop according to partly different principles. The gut's supporting tissue appears to acquire its regional identity early in development, and its precursor cells seem to be committed to specific future roles from an early stage. In contrast, the cells that later form the gut's own nervous system retain their developmental potential for longer and specialise at a later stage.
"Our method makes it possible to track how individual cells contribute to the formation of the gut during fetal development. This gives us a better understanding of how different cell types arise and are organised within the tissue," says Ulrika Marklund, Associate Professor at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet and corresponding author of the study.
The researchers also showed that the method can be used to alter gene activity during development. As a first example, they increased the activity of the gene regulator ASCL1, which resulted in the formation of more nerve cells in the gut.
"Because the technique can also be used for genetic manipulation, it gives us a tool to investigate how specific genes control the development of the different cell types in the gut," says Ulrika Marklund.
According to the researchers, this is the first time a method has combined the ability to label, study and genetically manipulate gut tissue in mice during fetal development. The study therefore provides both new knowledge about how the gut and its nervous system form and a new tool for future research.
In the longer term, the method could be used to investigate how disruptions early in fetal development affect the development of the gut and how such changes may contribute to congenital or chronic intestinal diseases.
The study was conducted in close collaboration with Emma Andersson's group at the Department of Cell and Molecular Biology at Karolinska Institutet.
Publication
Liu Z, Padmanabhan K, He J, Hector K, Semsch B, Sun J, Knoflach V, Giatrellis S, Lorentz J, Dallakyan K, Göritz C, Andersson ER, Marklund U
Proc Natl Acad Sci U S A 2026 Sep;123(37):e2614077123
