NGL-3 (Netrin G ligand 3) is a postsynaptic cell adhesion molecule that is a member of the NGL family. NGLs are proteins involved in the regulation of various steps in synapse formation. Members of this family share a common domain structure that contains: nine Leucine rich repeats (LRRs), an immunoglobulin (Ig) domain in the extracellular region, a single trans membrane domain and a cytoplasmic region that ends with a PDZ domain-binding motif. This motif mediates the interaction with PSD-95, an abundant postsynaptic scaffolding protein^1,2.

The NGL family is comprised of three proteins: NGL-1, 2, and 3. NGL-1 and NGL-2 interact through their extracellular domain with the GPI anchored membrane proteins Netrin G1 and G2 respectively^2-4. This interaction is important for regulation of structural and functional excitatory synapse development⁴.

NGL-3 trans-synaptically interacts with the leukocyte common antigen-related (LAR) protein which is well-known for its involvement in axon guidance and presynaptic differentiation. This interaction induces pre- and postsynaptic differentiation in contacting axons and dendrites, respectively, and regulates excitatory synapse formation^2,5.

Mice lacking NGL-3 (Ngl3^−/−) show markedly suppressed normal brain development and postnatal survival and growth⁶. NGL-3 overexpression and knockdown in cultured neurons result in bidirectional changes in the number of excitatory synapses and spontaneous excitatory synaptic transmission⁵.

NGL-3 mRNA and proteins are mainly detected in synaptic fractions of the brain and levels gradually increase during the first 3 weeks of postnatal rat brain development⁶.