Neurons can achieve intercellular communication through extracellular vesicles (exosomes) loaded with secretoneurin (SN), which further facilitate the developmental progression of gonadotropin-releasing hormone (GnRH) neurons, according to a recent study published in Science Bulletin.

The study was led by Professor HU Wei from the Institute of Hydrobiology (IHB) of the Chinese Academy of Sciences, in collaboration with the research group of Professor Vance L. Trudeau at the University of Ottawa in Canada.

The reproductive system of vertebrates is mainly governed by the hypothalamic-pituitary-gonadal (HPG) axis. As the core upstream constituent of the HPG axis, GnRH neurons synthesize and secrete GnRH neuropeptide, which functions as a core signaling substance dominating reproductive regulation across vertebrate species.

Identification of previously unreported upstream regulatory factors targeting GnRH neurons within the HPG axis holds profound implications for research on fish reproductive modulation, and also offers important reference for investigating olfactory and reproductive disorders including Kallmann syndrome triggered by aberrant GnRH neuron development.

By constructing the Tg(scg2a:mCherry/gnrh3:EGFP) double transgenic strain and conducting confocal microscopic observation, the research team verified that scg2a-positive cells present a tight spatial correlation with the distribution pattern of GnRH3 neurons in the brain. Genetic knockout of the scg2a gene results in an obvious decline in the number of GnRH3 neurons, whereas exogenous supplementation of SNa is capable of restoring the normal number of GnRH3 neurons in gene-deficient individuals.

In vivo time-lapse laser confocal imaging and exosome isolation and identification confirmed that exosomes secreted by scg2a-positive cells transport SNa and directly target GnRH3 neurons. This indicates that SNa mediates intercellular communication in the nervous system through exosomal delivery and plays a pivotal role in regulating the development of GnRH3 neurons.

Subsequent intervention assays using activators and inhibitors targeting the PI3K/Akt signaling pathway confirmed that exosome-transported SNa boosts the proliferation capacity and electrical excitability of GnRH3 neurons by activating the intracellular PI3K/Akt signaling cascade. Sustained activation of Akt signaling within GnRH3 neurons can effectively remedy the developmental abnormalities observed in scg2a mutant organisms.

Calcium signal detection and electrophysiological recording results further indicated that SNa significantly elevates calcium signal activity and discharge frequency of GnRH3 neurons in a PI3K/Akt pathway-dependent manner. Notably, such biological effects and underlying regulatory mechanisms are evolutionarily conserved in GnRH neurons of both zebrafish and mice.

Overall, this study elucidates that SN, an evolutionarily conserved neuropeptide encoded by SCG2, modulates GnRH neuron development by initiating the PI3K/Akt signaling pathway in GnRH3 neurons through exosome-dependent intercellular signal transmission.