Primordial germ cells experience increasing physical confinement and DNA damage during migration in the mouse embryo

To produce healthy offspring, an organism must pass on its genetic material with high fidelity. In many species, this is accomplished by primordial germ cells (PGCs), which give rise to sperm or eggs. PGCs are often specified far from the future gonads and must migrate through developing tissues to reach them. Failure to do so can result in infertility or germ cell tumors. While PGC migration is well characterized in some species, very little is known about their migration in mammalian embryos. Here, we performed dynamic and quantitative analyses of PGC migration from E7.5 to E9.5 in the mouse embryo, providing the first comprehensive study of the migratory characteristics of PGCs from their point of origin to the gonads. We demonstrate that migrating PGCs are influenced by the surrounding environment and, in contrast to other organisms, extend highly dynamic, actin-rich protrusions to navigate through extracellular matrix (ECM) barriers, and tight intercellular spaces. As PGCs migrate through increasingly confined spaces, they undergo significant nuclear deformation and become prone to nuclear rupture and DNA damage. Their migration under confinement may be aided in part by a depleted nuclear lamina that leads to wrinkled nuclear morphology. Our high-resolution and dynamic imaging approaches have uncovered an unexpected risk to genome integrity in migrating PGCs, with implications for DNA repair and adaptations in nuclear mechanics in PGCs.