Cohesin complex acts as molecular switch in neuron fate determination

Researchers at MIT have discovered that the cohesin protein complex, which organizes the three-dimensional structure of the genome, serves as a molecular switch determining whether certain developing neurons become adrenergic or GABAergic in the nematode C. elegans. The study, led by postdoc Dongyeop Lee in the laboratory of H. Robert Horvitz, was published in Science Advances.

C. elegans normally possesses two pairs of adrenergic neurons, known as RIM and RIC, which use tyramine and octopamine as neurotransmitters. Through a genetic screen, the team identified that mutations in the coh-1 gene, a component of cohesin, caused worms to produce extra RIM and RIC neurons. Similar effects occurred with other mutations disrupting cohesin function.

Further experiments showed that cohesin cooperates with the transcription factor EOR-1, the worm equivalent of human PLZF, to promote the development of GABA-producing neurons. When either cohesin or EOR-1 was impaired, precursor cells that would normally become GABAergic neurons adopted an adrenergic fate instead. This indicates that genome architecture directly influences neuronal identity decisions.

The findings have direct relevance to Cornelia de Lange syndrome, a rare developmental disorder caused by mutations in cohesin genes. Worms with cohesin mutations displayed severe developmental defects, including slow growth, movement difficulties, and reproductive problems, echoing features of the human syndrome.

The Horvitz lab has already identified suppressor mutations that can counteract the effects of impaired cohesin in worms, improving their health. The team is now working to identify the genes involved in this suppression to evaluate their potential as therapeutic targets for Cornelia de Lange syndrome.

Researchers are also investigating whether cohesin plays similar fate-determination roles in other neuron types and searching for additional molecular partners that collaborate with cohesin during development. Lee described the work as opening a new area of biology linking genome structure to cell fate specification.