NELL2 is a glutamatergic neuron-specific regulator for vesicular exocytosis

NELL2, a protein containing epidermal growth factor (EGF)-like repeats, is almost exclusively expressed in neurons, but the role it may play in neuronal function remains uncertain. We now show that NELL2 is selectively expressed in glutamatergic neurons throughout the brain, and that it enhances Ca²⁺-dependent glutamate release and Ca²⁺-activated vesicular exocytosis. Although NELL2 localizes mostly to the cytosol, it associates with the synaptic vesicle protein synaptophysin, excluding the SNARE protein synaptobrevin. A major glutamatergic function in the neuroendocrine brain is to enhance release of LHRH, the neurohormone controlling sexual development, at the time of puberty. In vivo disruption of NELL2 synthesis reduced LHRH release from the hypothalamus and delayed the initiation of puberty. These results identify NELL2 as a new component of glutamate exocytosis and provide evidence for its physiological involvement in a major, glutamatedependent process of neuroendocrine regulation.