Publication: The AMPK-related kinase NUAK1 regulates neuronal morphogenesis through the RNA splicing co-factor SON

Published in:

Authors: Martijn Kerkhofs, Géraldine Meyer-Dilhet, Hélène Polvèche, Sozerko Yandiev, Jacqueline Tait-Mulder, Sergio Lilla, David Sumpton, Daniel Murphy, Eun-Young Erin Ahn, Cyril Bourgeois, Evelyne Goillot, Julien Courchet

Summary

In recent years, alternative splicing emerged as a major mechanism controlling gene-regulatory networks during brain development, yet how alternative splicing is tuned to the dynamic alterations underlying neuronal maturation remains poorly understood. Here, we identified that NUAK1, an AMPK-related kinase linked to neurodevelopmental disorders, is a key regulator of alternative splicing in developing cortical neurons. Mechanistically, NUAK1 exerts its function through phosphorylation of the splicing co-factor SON, regulating a group of highly conserved splicing events in genes crucial for neurodevelopment. We demonstrate that SON plays an important role in cortical neuron development, which is consistent with the neurodevelopmental phenotypes observed in Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, a genetic disorder caused by SON haploinsufficiency. Together, our findings uncover a novel pathway involving NUAK1 and SON, which orchestrate a splicing program required for proper neuronal development.

Link to HAL – hal-05345384

Link to DOI – 10.1101/2025.10.10.681550