Human brain development triggered by two key signals

Molecular signals that give identity to cells in the early developing brain have been identified.

Researchers at Yale School of Medicine in New Haven, Connecticut, used brain organoids – 3D tissues created from human stem cells – to investigate signalling molecules called morphogens, which are known to govern early brain development. They discovered that how cells react to these morphogens varies not only between stem cells from different donors but also between cells from the same individual.

'This is a new chapter in understanding how we develop and how development can be influenced by genomic changes between people and by epigenetic modifications within individuals,' said study leader Professor Flora Vaccarino, co-senior author of the findings published in Cell Stem Cell.

The researchers looked at changes in gene expression in cells after exposing the organoids to two morphogens called WNT and Sonic Hedgehog. In the developing brain, WNT concentrations vary along a gradient on the top to bottom axis, while Sonic Hedgehog varies along the front to back axis. The investigators found that the different concentrations of these molecules in different locations within the organoid governed activity of certain genes. These in turn triggered development of brain cell types from different parts of the brain including the cerebellum, midbrain and the pons.

The researchers examined gene expression in nearly 200,000 separate cells from organoids using stem cells from seven different donors. The organoids were exposed to WNT and Sonic Hedgehog molecule gradients for five days to trigger the changes in gene expression.

'It was striking to see that the human brain development can be triggered by a relatively short exposure to two key signals,' said co-senior author Professor Andre Levchenko. 'This research opens the door to... understanding of a key developmental process that can be linked to specific human subjects in a much more precise manner than before.'

The authors acknowledged that this study is limited by its small sample size and sex bias, as the organoids were all created from stem cell lines from men. They stress the importance of characterising gene expression from a larger sample size which also includes organoids created from female stem cells.