In vivo DNA damage protection during cell migration across confining embryonic tissue environments

ABSTRACT: In physiology and in disease, cells often migrate through narrow spaces, such as leukocytes undergoing diapedesis or cancer cells during dissemination. Cultured cells under physical confinement can experience mechanical stress due to deformation of the nucleus. Nuclear deformation leads to loss of nuclear integrity and DNA damage, and it has been proposed to underlie cancer initiation and progression. In vivo, the consequences of physical confinement on physiological cell migration remain poorly understood. Here, we use the zebrafish neural crest as an in vivo model to address how multipotent embryonic cells respond to physical confinement during developmental migration. By measuring the size of extracellular spaces, we found that the level of tissue scale confinement increases from head to tail along the embryonic antero-posterior axis. Nuclear morphometrics analysis shows that neural crest experience dramatic nuclear deformation during their migration between adjacent tissues, which quantitatively scales with tissue confinement. By using complementary genetic and mechanical strategies to ablate the surrounding tissue, we observe a rescue of nuclear deformation in vivo. Surprisingly, we found that while deformation of the neural crest nucleus causes nucleo-cytoplasmic leakage, it does not cause nuclear envelope rupture or increase DNA damage even upon extreme deformations. Instead, confined migratory neural crest show decreased LaminB2 at the nuclear envelope. By perturbing LaminB2 expression levels, we discover that loss of LaminB2 facilitates fast recovery from deformation, while sustained expression of LaminB2 results in persistently deformed nuclei, highlighting a role for LaminB2 in nuclear shape deformability. Using a photoconversion and RNA-seq approach, we uncover upregulation of a large network of DNA repair genes in confined trunk neural crest, suggesting these stem cells might be resistant to confinement-induced mechanical stresses. In summary, we establish the neural crest as a physiological framework, uncovering dynamic adaptations to tissue confinement in vivo.

ORGANISM(S): Danio rerio

PROVIDER: GSE330051 | GEO | 2026/07/14

REPOSITORIES: GEO