Journal
HUMAN MOLECULAR GENETICS
Volume 31, Issue 5, Pages 674-691Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddab277
Keywords
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Funding
- Wellcome Trust ISSF Grant [097819]
- King's Health Partners Research and Development Challenge Fund
- Guy's and St Thomas' Charity
- Brain and Behavior Foundation [25957]
- European Autism Interventions (EU-AIMS)
- Innovative Medicines Initiative Joint Undertaking [115300]
- European Union
- EFPIA companies
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This study reveals a novel role for cell-adhesion proteins NLGN3 and NLGN4X in the development of neuronal architecture and uncovers the mechanism by which these proteins promote neuritogenesis in immature neurons.
The cell-adhesion proteins neuroligin-3 and neuroligin-4X (NLGN3/4X) have well described roles in synapse formation. NLGN3/4X are also expressed highly during neurodevelopment. However, the role these proteins play during this period is unknown. Here we show that NLGN3/4X localized to the leading edge of growth cones where it promoted neuritogenesis in immature human neurons. Super-resolution microscopy revealed that NLGN3/4X clustering induced growth cone enlargement and influenced actin filament organization. Critically, these morphological effects were not induced by autism spectrum disorder (ASD)-associated NLGN3/4X variants. Finally, actin regulators p21-activated kinase 1 and cofilin were found to be activated by NLGN3/4X and involved in mediating the effects of these adhesion proteins on actin filaments, growth cones and neuritogenesis. These data reveal a novel role for NLGN3 and NLGN4X in the development of neuronal architecture, which may be altered in the presence of ASD-associated variants.
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