The reproductive system of vertebrates is primarily regulated by the hypothalamic-pituitary-gonadal (HPG) axis. Gonadotropin-releasing hormone (GnRH) neurons serve as the core upstream component of the HPG axis, and the GnRH neuropeptide synthesized and secreted by these neurons acts as a key signaling molecule for reproductive regulation in vertebrates.

Exploring novel factors upstream of the HPG axis that regulate GnRH neurons is not only of great significance for research on fish reproductive regulation, but also provides valuable insights into the study of olfactory and reproductive dysfunctions (such as Kallmann syndrome) caused by abnormal development of GnRH neurons.

Recently, a research group led by Prof. HU Wei from the Institute of Hydrobiology (IHB) of the Chinese Academy of Sciences, collaborated with the team of Professor Vance L. Trudeau from University of Ottawa in Canada, uncovered neurons communicate via extracellular vesicles (exosomes) carrying secretoneurin, which in turn stimulates the development of gonadotropin-releasing hormone (GnRH) neurons. This work was published in Science Bulletin.

With generating Tg(scg2a:mCherry/gnrh3:EGFP) double transgenic line and confocal imaging, they found that scg2a-positive cells are closely correlated with the distribution of GnRH3 neurons in the brain. Knockout of the scg2a gene leads to a significant reduction in the number of GnRH3 neurons, while supplementation of SNa can restore the number of GnRH3 neurons in mutant 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.

Treatment with the PI3K/Akt pathway activator and inhibitor demonstrated that exosome-delivered SNa promotes the proliferation and excitability of GnRH3 neurons by activating the PI3K/Akt signaling pathway in these neurons. Constitutive activation of Akt in GnRH3 neurons can rescue the developmental defects of scg2a mutants.

Calcium imaging and electrophysiological recordings showed that SNa markedly enhances the calcium signaling and firing frequency of GnRH3 neurons via the PI3K/Akt pathway. Moreover, this biological function and regulatory mechanism are conserved in GnRH neurons of both zebrafish and mice.

In summary, this study reveals that SN, a conserved neuropeptide derived from SCG2, regulates GnRH neuron development by activating the PI3K/Akt pathway in GnRH3 neurons through exosome-mediated intercellular communication.

(Editor: MA Yun)