Puberty, that awkward phase when boys and girls are primed for their sexual reproductive years as men and women, appears to be triggered by the brain’s own version of “It takes two to tango,” whereby a signal literally gets turned on by a molecule that is produced by a gene aptly named KiSS-1.

The turn-on occurs suddenly in a region of the brain called the hypothalamus just as puberty begins, according to a study published in last week’s online edition of the Proceedings of the National Academy of Sciences (PNAS).

Until now, little had been known about what instigates the cascade of hormone secretions that, over time, produces puberty’s tell-tale physical changes, including the development of breasts in girls and voice change in boys. As such, this research begins to answer some of the most vexing questions about human development: What causes puberty to begin? How is it that the full repertoire of reproductive hormones can exist at birth, go into hiding at about four to six months of age, then reemerge in full force some 10 to 12 years later?

“Puberty is critical to human development. And while there is a fairly good understanding of how the endocrine system regulates the hormones involved, just how and when the brain activates this process has been a great mystery,” noted the study’s lead author, Tony Plant, a professor in the Pitt School of Medicine’s Department of Cell Biology and Physiology and its Department of Obstetrics, Gynecology, and Reproductive Sciences.

“An appreciation of puberty’s deep-seated neurobiological mechanisms could, for instance, help prevent precocious or delayed puberty from occurring in some children,” added Plant, who also directs the medical school’s Center for Research in Reproductive Physiology.

The research, performed in collaboration with teams at Harvard University’s Massachusetts General Hospital and the Oregon National Primate Research Center, builds on the discovery made independently by both Harvard and French researchers that a gene called GPR54 is defective in children with a rare disorder that inhibits puberty’s onset. To better understand what role GPR54 plays in the initiation of puberty, as well as learn about KiSS-1, which in earlier rodent studies had been identified as a molecule that activates a signal receptor of GPR54, the researchers looked to the nonhuman primate, the only animal with a reproductive system like that of a human.

The onset of puberty becomes official when gonadotropin-releasing hormone (GnRH) is secreted and sets off a chain reaction of chemical messages. Inside the hypothalamus, nerve cells release GnRH in a ‘round-the-clock, pulsatile fashion. With each secretion, the pituitary gland is stimulated to secrete its own messengers, lutenizing hormone (LH) and follicle-stimulating hormone (FSH), directly into the circulation. In turn, these rising levels of LH and FSH cause the testes and ovaries to produce the sex hormones testosterone and estradiol, the culprits responsible for the physical changes and emotional baggage of male and female puberty.

“We now have very good evidence that the GPR54 gene and its switch, the kisspeptin protein molecule produced by KiSS-1, are key to the initiation of puberty, when GnRH is released,” Plant said. “However, it’s unlikely that they act alone. Other signaling systems, some of which have probably yet to be identified in humans, help control GnRH release in primates.”

Besides learning that GPR54 and KiSS-1 are expressed inside the hypothalamus of primates at the time of puberty, the researchers also found that by giving animals kisspeptin they could, essentially, wake up the reproductive hormones from their childhood hibernation. Within 30 minutes of kisspeptin being administered to male monkeys, LH, one of the hormones stimulated by GnRH secretion, was no longer dormant, with levels 25 times higher than its baseline of zero.

In addition to Plant, authors of the PNAS paper include Muhammad Shahab, formerly a fellow working with Plant and now at Quaidi-i-Azam University in Islamabad, Pakistan; and researchers at the Oregon National Primate Research Center and Harvard’s Massachusetts General Hospital.

Their research was supported by the National Institute of Child Health and Human Development of the National Institutes of Health.