The outer kinetochore components KNL-1 and Ndc80 complex regulate axon and neuronal cell body positioning in the C. elegans nervous system

The central nervous system (CNS) is comprised of the brain and spinal cord and is assembled during early embryonic development in a process called neurodevelopment. Signals are sent across the CNS via a network of nerve cells, also known as neurons, to control how we move, feel, think and learn. In this paper, the Cheerambathur lab at the University of Edinburgh has explored the role of the protein network, KMN (consisting of KnI-1, Mis12 and Ndc80) in neurodevelopment. The KMN is already known to have an important role in mitosis, a process in which genetic material is divided in half. More specifically, the KMN works as part of the kinetochore, a structure which rope-like proteins called spindle microtubules attach to and pull chromosome pairs apart. Here, the Cheerambathur lab explore additional functions of the KMN. They carried out their research in a C. elegans worm model to replicate the human CNS. C. elegans has a very simple and well-known nervous system structure, which makes it a great model for studying neurodevelopment.

Firstly, they used molecular biology techniques to deplete the protein KNL-1, a component of KMN, in the worm. They found defects in the placement of a specific region of neurons called the axon. They then examined worms with mutations in genes with known cellular functions and found that worms with mutations in axon positioning genes resembled those with deleted KNL-1. They saw the axons developing more posteriorly than they should.  They also utilized a split-GFP system to tag KNL-1  so they could track its location during the axon development, specifically in the head neurons. Together this suggested that KNL-1 has a role in axon development and guidance, specifically in correct placement of the axon.

They then replaced the depleted KNL-1 with versions of KNL-1  that had missing areas of the protein to determine the function of these different regions. They found that the region important for KNL-1 molecular signalling was required for proper neurodevelopment as without this region, they noticed the same neurodevelopment faults as in the KNL-1 depleted worms. Depleting the other KMN component NDC80 showed similar characteristics. This strongly suggested that both signalling and microtubule binding interface of the KMN network are important for successful neurodevelopment.

Overall, this work has made significant advances into understanding the novel non-canonical neuronal role of the outer kinetochore proteins, elucidating further the molecular process of neurodevelopment. Additional research in this field could help apply these understandings to medicine and therapeutics.