cpg15 and cpg15-2 constitute a family of activity-regulated ligands expressed differentially in the nervous system to promote neurite growth and neuronal survival

Many ligands that affect nervous system development are members of gene families that function together to coordinate the assembly of complex neural circuits. cpg15/neuritin encodes an extracellular ligand that promotes neurite growth, neuronal survival, and synaptic maturation. Here we identify cpgl5-2 as the only paralogue of cpg15 in the mouse and human genome. Both genes are expressed predominantly in the nervous system, where their expression is regulated by activity. cpg15-2 expression increases by more than twofold in response to kainate-induced seizures and nearly fourfold in the visual cortex in response to 24 hours of light exposure following dark adaptation. cpg15 and cpgl5-2 diverge in their spatial and temporal expression profiles. cpgl5-2 mRNA is most abundant in the retina and the olfactory bulb, as opposed to the cerebral cortex and the hippocampus for cpgl5. In the retina, they differ in their cell-type specificity. cpgl5 is expressed in retinal ganglion cells, whereas cpg15-2 is predominantly in bipolar cells. Developmentally, onset of cpg15-2 expression is delayed compared with cpgl5 expression. CPG15-2 is glycosylphosphatidylinositol (GPI) anchored to the cell membrane and, like CPG15, can be released in a soluble-secreted form, but with lower efficiency. CPG15 and CPG15-2 were found to form homodimers and heterodimers with each other. In hippocampal explants and dissociated cultures, CPG15 and CPG15-2 promote neurite growth and neuronal survival with similar efficacy. Our findings suggest that CPG15 and CPG15-2 perform similar cellular functions but may play distinct roles in vivo through their cell-type- and tissue-specific transcriptional regulation.