Researchers from the Icahn School of Medicine at Mount Sinai have identified a gene that controls how the skull is shaped in early development. Their findings will hopefully further our understanding of early developmental disorders in infants.
The importance of skulls
Our skulls are incredibly important to our health – after all, they do protect our brains. Skulls are composed of several bone plates which fuse together at joints, known as sutures. These are fibrous bands of tissue that are crucial for new-born development. The flexibility of sutures allows the brain to grow rapidly in infancy. Eventually, at around two years of age, sutures become bone.
However, in some babies, sutures close too early. This is due to a developmental disorder called craniosynostosis, whereby around 25% of cases are linked to genetic mutations. Craniosynostosis affects 1 in 2,500 births in the United States and can lead to neurological disorders because the brain cannot grow properly. The condition most commonly affects the coronal suture, which connects the front and middle bone plates.
Gene expression during skull development
A team from Mount Sinai investigated cells from the coronal suture in mice, to better understand any genetic changes that occur during early development. The researchers carried out single-cell RNA-seq analysis, allowing them to analyse the gene expression of cells in mice that were just about to be born.
The scientists noticed one gene in particular, Hhip, which encodes the Hedgehog interacting protein (HHIP). HHIP inhibits proteins in the Hedgehog signalling pathway. Hedgehog proteins have important roles in regulating embryonic development, including promoting bone growth.
In this study, the researchers found that all mice with normal skull development had enriched levels of Hhip expression. Hhip levels were particularly high in suture mesenchyme. This is loose connective tissue comprised of stem cells, which eventually differentiate into osteoblasts and synthesise bone. Conversely, mice that lacked the Hhip gene had much lower levels of mesenchymal tissue within their sutures. Instead, the team found that developing bones were closer together than in Hhip-expressing mice. As a result, Hhip-negative mice had distinctively differently shaped skulls.
These results suggest that normal skull development requires inhibition of Hedgehog signalling. A possible explanation could be that mice without Hhip have uninhibited Hedgehog signalling and so differentiation of mesenchymal cells into osteoblasts is promoted too quickly. This would lead to bone development and premature closing of the sutures.
Prior to this work, the relevance of HHIP to skull development was unknown. Excitingly, researchers can now carry out further investigations into how Hedgehog signalling and its inhibition may influence suture development. In addition, this study was done in mice. Therefore, future work is needed to discover whether similar mechanisms occur in humans. Hopefully, this will allow scientists to better understand craniosynostosis and, subsequently, develop novel relevant treatments.