The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour

Castroflorio, Enrico; den Hoed, Joery; Svistunova, Daria; Finelli, Matt�a J.; Cebrian-Serrano, Alberto; Corrochano, Silvia; Bassett, Andrew R.; Davies, Benjamin; Oliver, Peter L.

Abstract

Members of the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) protein family are associated with multiple neurodevelopmental disorders, although their exact roles in disease remain unclear. For example, nuclear receptor coactivator 7 (NCOA7) has been associated with autism, although almost nothing is known regarding the mode-of-action of this TLDc protein in the nervous system. Here we investigated the molecular function of NCOA7 in neurons and generated a novel mouse model to determine the consequences of deleting this locus in vivo. We show that NCOA7 interacts with the cytoplasmic domain of the vacuolar (V)-ATPase in the brain and demonstrate that this protein is required for normal assembly and activity of this critical proton pump. Neurons lacking Ncoa7 exhibit altered development alongside defective lysosomal formation and function; accordingly, Ncoa7 deletion animals exhibited abnormal neuronal patterning defects and a reduced expression of lysosomal markers. Furthermore, behavioural assessment revealed anxiety and social defects in mice lacking Ncoa7. In summary, we demonstrate that NCOA7 is an important V-ATPase regulatory protein in the brain, modulating lysosomal function, neuronal connectivity and behaviour; thus our study reveals a molecular mechanism controlling endolysosomal homeostasis that is essential for neurodevelopment.

Citation

Castroflorio, E., den Hoed, J., Svistunova, D., Finelli, M. J., Cebrian-Serrano, A., Corrochano, S., …Oliver, P. L. (2021). The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour. Cellular and Molecular Life Sciences, 78(7), 3503-3524. https://doi.org/10.1007/s00018-020-03721-6

• Journal Article Type: Article
• Acceptance Date: Nov 24, 2020
• Online Publication Date: Dec 19, 2020
• Publication Date: Apr 1, 2021
• Deposit Date: Dec 23, 2020
• Publicly Available Date: Jan 14, 2021
• Journal: Cellular and Molecular Life Sciences
• Print ISSN: 1420-682X
• Electronic ISSN: 1420-9071
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 78
• Issue: 7
• Pages: 3503-3524
• DOI: https://doi.org/10.1007/s00018-020-03721-6
• Keywords: Molecular Medicine; Cell Biology; Molecular Biology; Pharmacology; Cellular and Molecular Neuroscience
• Public URL: https://nottingham-repository.worktribe.com/output/5172895
• Publisher URL: https://link.springer.com/article/10.1007/s00018-020-03721-6
• Additional Information: Received: 5 June 2020; Revised: 8 November 2020; Accepted: 24 November 2020; First Online: 19 December 2020; : ; : The authors declare that there are no conflicts of interest. The funding institution had no role in data acquisition, analysis or decision to publish the results.; : Animals were generated and maintained under UK Home Office Project Licences 30/2966, 30/3353 and P7133CD66 with local ethical guidelines issued by the University of Oxford and the Medical Research Council Harwell Institute.