Neuroligin-3, neuroligin-4X (NLGN3/4X) and neurexin-1 (NRXN1) are cell adhesion molecules (CAMs) with established roles in synaptogenesis during later stages of human neurodevelopment. CAMs also play key roles in neuritogenesis, particularly via clustering in the growth cone. Gene mutations in CAMs such as NLGNs and NRXNs are frequently associated with autism spectrum disorder (ASD). However, little is known about these proteins in earlier stages of human neurodevelopment such as neuritogenesis. This thesis reviews the evidence linking CAMs in neurite outgrowth and the growth cone to ASD pathogenesis, then demonstrates novel findings regarding NLGN3/4X and NRXN1 CAMs in early human neurodevelopment. This thesis showed 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 overexpression 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 (PAK1) 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. Furthermore, cortical neurons generated from ASD patient induced pluripotent stem cells with deletions in NRXN1 demonstrated NRXN1 also promotes neurite outgrowth, potentially via differential regulation of specific NRXN1 isoforms. These data reveal novel roles for NLGN3/4X and NRXN1 in the development of neuronal architecture, which may be altered in the presence of ASD-associated variants.
Understanding the role of neuroligin-3, neuroligin-4X, and neurexin-1 in early human neurodevelopment: implications for Autism Spectrum Disorder
Gatford, N. (Author). 1 Feb 2021
Student thesis: Doctoral Thesis › Doctor of Philosophy