The Protein Behind Chromosome Structure Regulation
Researchers from Osaka University have identified the cohesin protein complex as a key factor in controlling the chromosome structure that underlies the formation of nerve cell networks. Using mouse models, the team were able to demonstrate that mutations affecting the complex lead to similar symptoms to the developmental disorder Cornelia de Lange syndrome (CdLS). The research was published in the Journal of Experimental Medicine today.
In cells, DNA is packaged into complexes called chromatin by histone proteins. During cell division, these complexes are further compacted into chromosomes, which have highly distinctive structures. Abnormalities in this defined structure have been shown to affect gene expression during development of nerve cell networks.
This research now shows how cohesin, a protein complex that manages gene expression and chromatin structure, has to be expressed at sufficient levels in mice brains to enable healthy development. Mutations in genes that affect the cohesin complex have been shown to be linked to CdLS, and the team suspected that this was due to structural defects instead of incorrect chromosome separation, which cohesin is also involved in.
To test their theory, the team inactivated expression of the Smc3 gene in mice, which codes for one part of the cohesin complex. Their results varied depending on which cell type they performed the mutations in, such as cleft palates, small skulls, or higher brain function abnormalities, but the general phenotypes observed were very similar to CdLS.
“Mice with reduced expression of cohesin had abnormalities in the development of nerve cell branches and junctions in the cerebral cortex, the grey matter of the brain that is responsible for consciousness and memory,” said Yuki Fujita, first author of the paper. “They were also much more anxious than control mice in a range of behavioural tests.”
Anxiousness is also a symptom of CdLS, further connecting their results.
“We also found that reduced cohesin led to changes in the expression of genes involved in nerve cell development and the response to an immune signalling protein,” said Toshihide Yamashita, co-author. “These changes were related to the neuronal and behavioural signs we saw in the mice.”
The results not only demonstrate how cohesin interacts with correct development, it also indicates that mice can act as suitable models for CdLS investigations. This could be of significant use to other groups hoping to better understand the condition.