Researchers at the University of Ottawa and the Institute of Hydrobiology of the Chinese Academy of Sciences have discovered a new role for reproductive hormone secretoneurin (SN) and, for the first time, explained how it travels between brain cells to shape the development of the reproductive system.
The findings, published in two studies, show that SN stimulates the growth and activity of neurons that control reproduction, and does so through a previously unknown delivery mechanism: tiny biological packages called exosomes.
The master switch for reproduction
Gonadotropin-releasing hormone (GnRH) neurons are the master regulators of reproduction in all vertebrates, from fish to humans. They trigger a hormonal chain reaction that leads to ovulation in females and sperm production in males. When these neurons don't develop properly, the result can be hypogonadotropic hypogonadism. This is a condition causing poor development of the reproductive organs in both sexes, It leads to infertility or Kallmann syndrome, which combines infertility with the loss of sense of smell.
"GnRH controls many aspects of reproduction by regulating hormones in the pituitary gland," says Vance Trudeau, Full Professor in uOttawa's Department of Biology and University Research Chair in Neuroendocrinology. "Understanding what drives the development of GnRH neurons is fundamental; without them, the entire reproductive system fails to function."
Microscopic delivery bags carry the signal
Using zebrafish as a model, the teams showed that neurons producing a protein called secretogranin-2 (SCG2) package SN into exosomes (microscopic, membrane-bound vesicles) and release them. These molecular delivery parcels travel to neighbouring GnRH neurons, stimulating their proliferation. Zebrafish lacking the SCG2 gene had roughly half the normal number of GnRH neurons and showed severe reproductive defects as adults, with females largely unable to ovulate normally.
"The critical question we answered is how SN is delivered from one cell to another," explains Professor Trudeau. "Discovering that it travels via exosomes is big news in the field, it's a completely new mechanism for how reproductive signals are communicated in the developing brain."
"We've identified a hormone that is conserved from fish to mammals and shown, for the first time, that it reaches GnRH neurons via exosomes"- Vance Trudeau, Full Professor, uOttawa's Department of Biology & University Research Chair in Neuroendocrinology
From fish to mice: a conserved system
A parallel study in mice confirmed that SN levels peak alongside GnRH in the hypothalamus just before ovulation, and that SN directly activates the gene that encodes GnRH in mouse brain cells. The conservation of this system across two very different vertebrate species underscores its fundamental biological importance.
"These two studies together tell a compelling story," describes Professor Trudeau. "We've identified a hormone that is conserved from fish to mammals and shown, for the first time, that it reaches GnRH neurons via exosomes.They are bubble-like sacs that acts as a hormone cargo system. This opens entirely new directions for understanding why some people are born with reproductive disorders."
Implications for human reproductive disorders
The SCG2 gene is currently absent from the clinical genetic panels used to diagnose hypogonadotropic hypogonadism and Kallmann syndrome, and the researchers say it warrants investigation as a candidate gene in patients whose condition has no known genetic cause.
"SCG2 is not yet on the gene panels clinicians use when diagnosing these conditions," notes Professor Trudeau. "Our work positions it as a strong candidate for future investigation; it could help explain cases that currently have no genetic explanation."
The first study, titled "Periovulatory neurohormone dynamics reveal an association between secretoneurin and GnRH across the mouse estrous cyclenorth_eastexternal link", was published in Frontiers in Endocrinology. The second study, titled "Exosomal secretoneurin regulates proliferation of gonadotropin-releasing hormone neuronsnorth_eastexternal link", was published in Science Bulletin.
