Neuropilins and Their Ligands Are Important in the Migration of Gonadotropin-Releasing Hormone Neurons

Abstract

Gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus play an important role in reproductive function. These cells originate in the nasal compartment and migrate into the basal forebrain in association with olfactory/vomeronasal nerves in embryonic life in rodents. Here, we studied the role of neuropilins and their ligands, semaphorins, in the development of the olfactory-GnRH system. We focused on Neuropilin-2 knock-out (Npn-2 ؊/؊ ) mice, because they are known to display defasciculation of olfactory nerves and reduced fertility. We found a significant decrease in the number of GnRH neurons in the hypothalamus and a marked reduction in their gonadal size. We then observed an abnormal increase of GnRH neurons in the noses of Npn-2 ؊/؊ mice, indicating that these cells failed to migrate into the forebrain. However, because neuropilins and semaphorins are involved in events of neuronal migration in the brain, we asked whether the observed reduction in GnRH neurons was directly attributable to the action of these molecules. Using fluorescenceactivated cell sorting and reverse transcription-PCR on mRNA derived from embryonic green fluorescent protein (GFP)-GnRH transgenic mice, we found expression of class 3 semaphorins and their receptors (neuropilin-1/2 and plexin-A1) in GnRH neurons. Furthermore, double-immunofluorescence experiments showed that migrating GnRH neurons, as well as associated olfactory fibers, express Npn-2 in the nasal region. We then used a line of immortalized GnRH neurons (GN11 cells) that display the same expression patterns for semaphorins and their receptors as GFP-GnRH cells and found that class 3 semaphorins and vascular endothelial growth factors modulate their migratory activity. These studies provide support for the direct involvement of neuropilins and their ligands in the establishment of the GnRH neuroendocrine system.

Development of the neurons controlling fertility in humans: new insights from 3D imaging and transparent fetal brains

“…S1A-D). NRP2, the receptor for semaphorin 3F, is highly expressed by a subset of vomeronasal sensory neurons in rodent embryos and along vomeronasal axons innervating the AOB (Cariboni et al, 2007;Cloutier et al, 2002). Moreover, Nrp2 −/− mice display a GnRH migratory defect followed by reduced fertility and hypogonadism, supporting the direct involvement of neuropilins and their ligands in the establishment of the GnRH neuroendocrine system (Cariboni et al, 2007).…”

COUP-TFII controls amygdala patterning by regulating neuropilin expression

“…Consistently, although the expression of Nrp genes is greatly reduced in the mutants, it is the Pax6 + cells originated from the CGE that are severely affected (Figs 4,5;supplementary material Figs S6,S9). It has been reported that Nrp genes are required to mediate the migration of the GABAergic interneuron, cortical neuron, GnRH neuron and facial nerve neuron Chen et al, 2008;Cariboni et al, 2007;Schwarz et al, 2004). In addition to the cell migration, Nrp genes also play crucial roles in axon guidance.…”

Neuropilin, you gotta let me know

“…42 Adult Nrp2-null mice have fewer GnRH neurons in the hypothalamus, and this is accompanied by infertility. 43 Because Sema3f-and Nrp2-null mice have defasciculated olfactory nerves, 44,45 the GnRH defect is at least in part due to abnormal cell migration on a defective axonal substrate. However, GnRH neurons themselves also express NRP2, and they are repelled by SEMA3F in vitro.…”

“…However, GnRH neurons themselves also express NRP2, and they are repelled by SEMA3F in vitro. 43 This raises the possibility that SEMA3F/ NRP2 signaling may play a second, more direct role in GnRH neuron guidance. Finally, GnRH neurons express NRP1 and respond to VEGF164 and SEMA3A in vitro, 43 and loss of SEMA3A results in guidance errors of subsets of olfactory axons.…”

“…43 This raises the possibility that SEMA3F/ NRP2 signaling may play a second, more direct role in GnRH neuron guidance. Finally, GnRH neurons express NRP1 and respond to VEGF164 and SEMA3A in vitro, 43 and loss of SEMA3A results in guidance errors of subsets of olfactory axons. 46 However, the physiological significance of NRP1 signaling in GnRH patterning has not yet been investigated.…”