The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour
| Autor: | Alberto Cebrian-Serrano, Benjamin Davies, Enrico Castroflorio, Andrew R. Bassett, Peter L. Oliver, Daria M. Svistunova, Mattéa J. Finelli, Joery den Hoed, Silvia Corrochano |
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| Rok vydání: | 2020 |
| Předmět: |
Nervous system
Vacuolar Proton-Translocating ATPases Mouse Protein family Autism Nuclear Receptor Coactivators Neurodevelopment V-ATPase Endosomes Biology Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Lysosome Coactivator medicine Animals Behaviour Molecular Biology 030304 developmental biology Mice Knockout Neurons Pharmacology Regulation of gene expression 0303 health sciences Behavior Animal Cell Biology Neuron Cell biology Mice Inbred C57BL Disease Models Animal Oxidative Stress medicine.anatomical_structure Nuclear receptor Neurodevelopmental Disorders Molecular Medicine Female Original Article Lysosomes 030217 neurology & neurosurgery |
| Zdroj: | Cellular and Molecular Life Sciences |
| ISSN: | 1420-9071 1420-682X |
| Popis: | 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. Graphic abstract |
| Databáze: | OpenAIRE |
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