Shedding of neurexin 3 beta 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 Nrxn3 beta is processed by the metalloproteases ADAM10, ADAM17, and by the intramembrane-cleaving protease.-secretase, producing secreted neurexin3 beta (sNrxn3 beta) and a single intracellular domain (Nrxn3 beta-ICD). We further completed the full characterization of the sites at which Nrxn3 beta is processed by these proteases. Supporting the physiological relevance of the Nrxn3 beta processing, we demonstrate in vivo a significant effect of the secreted shedding product sNrxn3 beta on the morphological development of adult newborn neurons in the mouse hippocampus. We show that sNrxn3 beta produced by the cells of the dentate gyrus increases the spine density of newborn neurons whereas sNrxn3 beta produced by the newborn neuron itself affects the number of its mossy fiber terminal extensions. These results support a pivotal role of sNrxn3 beta in plasticity and network remodeling during neuronal development.