Nanoscopic Clustering of Neuroligin-3 and Neuroligin-4X Regulates Growth Cone Organization and Size

Abstract

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 itpromoted neuritogenesis in immature human neurons. Super-resolution microscopyrevealed that NLGN3/4X clustering induced growth cone enlargement and influenced actin filament organization. Critically, these morphological effects were not induced by Autism spectrum condition (ASC)-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. 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.

Combined omic analyses reveal novel loss-of-function NLGN3 variants in GnRH deficiency and autism

“…Because NLGN3 promotes neuritogenesis in human neural progenitor cells (27), we studied the effect of WT or mutant NLGN3 proteins on GnRH neuron morphology and neurite outgrowth by overexpression experiments in GN11 cells, as previously described (28). NLGN3 WT promoted the formation of several protrusions, with cells displaying an increased spreading compared to GFP-transfected controls ( Figure 7C ).…”

“…Because NLGN3 promotes neuritogenesis in human neural progenitor cells (27), we studied the effect of WT or mutant NLGN3 proteins on GnRH neuron morphology and neurite outgrowth by overexpression experiments in GN11 cells, as previously described (28). NLGN3…”

Xist induction following p53 disability features Nlgn4x modulation.

“…These data demonstrate layered transcriptional and epigenetic changes that follow abrogation of tumor suppression in humans, with an implication that these changes and the vulnerabilities that accompany them will be physiologically more relevant in females, but potentially important for patients of either sex with solid tumors resulting from loss of p53, in the case of a non-coding RNA with potent epigenetic modulatory properties (7)(8)(9). Neuroligin-4x, a neural cell adhesion molecule, has been described to regulate growth cone size and organization (5,6)…”