NELL2, a neuron-specific EGF-like protein, is selectively expressed in glutamatergic neurons and contributes to the glutamatergic control of GnRH neurons at puberty

NELL2, a protein containing EGF-like repeats, is almost exclusively expressed in the nervous system. In the mammalian brain, NELL2 expression is mostly neuronal. NELL2 was previously found to be a secreted protein that functions during embryonic development as a neuronal differentiation and survival factor. We now show that the Nell2 gene is selectively expressed in the two major subtypes of glutamatergic neurons described in the postnatal brain: those containing the vesicular glutamate transporter 1 and those expressing vesicular glutamate transporter 2. No Nell2 mRNA is detected in GABAergic neurons. Likewise, GnRH neurons are devoid of NELL2. During prepubertal development of the female rat, Nell2 mRNA abundance increases selectively in the medial basal hypothalamus, reaching maximal values at the end of the juvenile period, to decline at the time of puberty to intermediate levels. Similar, but less pronounced changes are observed in the preoptic area, but they are absent in the cerebral cortex. A well-established glutamatergic function in the neuroendocrine brain is to enhance release of GnRH, the neurohormone controlling sexual development and the time of puberty. In vivo disruption of NELL2 synthesis via intraventricular administration of antisense oligodeoxynucleotides reduced GnRH release from the medial basal hypothalamus and delayed the initiation of female puberty. These results identify NELL2 as a new component of glutamatergic neurons and provide evidence for its physiological involvement in a major, glutamate-dependent, process of neuroendocrine regulation.