Wrinkles in time
Karzbrun is a physicist by training, and he naturally turned to physical models for the behavior of elastic materials to understand the formation of the wrinkles. Folds or wrinkles in a surface are the result of mechanical instability – compression forces applied to some part of the material. So for example, if there is uneven expansion in one part of the material, another part might be forced to fold in order to accommodate the pressure. In the organoids, the scientists found such mechanical instability in two places: The cytoskeleton – the internal skeleton – of the cells in the center of the organoid contracted; and the nuclei of the cells near the surface expanded. Or, to think of it another way, the outside of the “pita” grew faster than its inside.
While this achievement was impressive, Reiner was not convinced that the wrinkles in the organoids were really modeling the folds in a developing brain. So the group grew new organoids, this time bearing the same mutations carried by babies with smooth brain syndrome. Reiner had identified this gene – LIS1 – back in 1993, and has investigated its role in the developing brain and in the disease, which affects one in 30,000 births. Among other things, the gene is involved in the migration of nerve cells to the brain during embryonic development, and it also regulates the cytoskeleton and molecular motors in the cell.
The organoids with the mutated gene grew to the same proportions as the others, but they developed few folds and the ones they did develop were very different in shape from the normal wrinkles. Working on the assumption that differences in the physical properties of the cell were responsible for these variations, the group investigated the organoid’s cells with atomic force microscopy, with the help of Dr. Sidney Cohen of the Chemical Research Support Department. By measures of elasticity, the normal cells were about twice as stiff as the mutated ones, which were basically soft. Reiner: “We discovered a significant difference in the physical properties of cells in the two organoids, but we observed difference in their biological properties as well. For example, the nuclei in the centers of the mutant organoids moved more slowly, and we saw significant differences in gene expression.”
Gif: As the organoid develops, the tissue in the outer part folds in a manner similar to those in the developing brain.
#stemcells #brainorganoids #lissencephaly #brainwrinkles #geneexpression #braindevelopment #neuroscience