Shedding of neurexin 3β ectodomain by ADAM10 releases a soluble fragment that affects the development of newborn neurons.

Neurexins are transmembrane synaptic cell adhesion molecules involved in the development and maturation of neuronal synapses. In the present study, we report that Nrxn3β is processed by the metalloproteases ADAM10, ADAM17, and by the intramembrane-cleaving protease γ-secretase, producing secreted neurexin3β (sNrxn3β) and a single intracellular domain (Nrxn3β-ICD). We further completed the full characterization of the sites at which Nrxn3β is processed by these proteases. Supporting the physiological relevance of the Nrxn3β processing, we demonstrate in vivo a significant effect of the secreted shedding product sNrxn3β on the morphological development of adult newborn neurons in the mouse hippocampus. We show that sNrxn3β produced by the cells of the dentate gyrus increases the spine density of newborn neurons whereas sNrxn3β produced by the newborn neuron itself affects the number of its mossy fiber terminal extensions. These results support a pivotal role of sNrxn3β in plasticity and network remodeling during neuronal development.