Our brains rely on tiny molecular “tags” to control how proteins behave. One important type of tag, called ubiquitin, helps regulate how cells of the nervous system grow, connect, and communicate. A group of proteins known as HERC E3 ubiquitin ligases plays a key role in this ubiquitination process. Mutations in HERC genes have been linked to conditions such as autism and developmental disorders, highlighting their importance for brain development. However, exactly how they affect brain cells is not yet clear.
In this project, we use a model organism, the microscopic worm C. elegans, to study those genes. By understanding how these proteins work in living organisms, we aim to uncover basic principles of how the brain develops and functions, and to provide new insights into neurological disorders.
Ubiquitination is a fundamental post-translational modification that regulates protein stability, trafficking, and signalling across the nervous system. Among the enzymes that mediate this process, the HERC family of HECT domain E3 ubiquitin ligases stands out for its evolutionary conservation and high expression in the mammalian brain. Despite this, the roles of HERC ligases in neurons remain largely unexplored.
Human genetic studies have linked mutations in HERC1 and HERC2 to neurodevelopmental conditions, including autism spectrum disorder, schizophrenia, and developmental delay. However, the cellular and molecular mechanisms by which these ligases influence neuronal differentiation, synaptic function, circuit assembly, and behaviour remain poorly understood.
This project uses the nematode Caenorhabditis elegans as a powerful in vivo model to address this gap. Unlike mammals, C. elegans encodes a single conserved HERC orthologue, herc-1, which is broadly expressed in the nervous system, providing a simplified system for dissecting its function.
Our goal is to define the cellular, molecular, and behavioural roles of herc-1 in vivo. By characterising its expression, localisation, and functional impact in the nervous system, this work will deliver the first comprehensive understanding of HERC ligase activity in an intact organism. Ultimately, this research aims to uncover fundamental links between ubiquitin signalling, neural development, and behaviour, and to provide new insights into the mechanisms underlying HERC-associated neurodevelopmental disorders.