NGL-2 Is a New Partner of PAR Complex in Axon Differentiation

Neuronal polarization is pivotal for neural network formationduring brain development. Axondifferentiation is a hallmark of initial neuronal polarization. Here, we report that the leucine-rich repeat-containing protein netrin- Gligand-2 (NGL-2) as a polarity regulator that localizes asymmetrically in rat hippocampal neurons and is required for differentiation of the future axon. NGL-2 was associated with PAR complex, and this interaction resulted in local stabilization of axonalmicrotubules. Further study showed that the C terminal of NGL-2 binds to the PDZ domainof PAR6, and NGL-2 interacts with PAR3 and atypical PKCζ (aPKCζ), with PAR6 acting as a bridge or modifier. Then, NGL-2 regulates the local stabilization of microtubules and promotes axondifferentiation by the aPKCζ/microtubule affinity-regulating kinase 2 pathway. These findings reveal the critical role of NGL-2 in regulating axondifferentiation in rat hippocampal neurons and reveal a novel partner of the PAR complex.