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N energy research initiative has a shot at receiving backing by the Administration, Joel Parriott, who helps the White House Office of Management and Budget oversee the budget for DOE’s Office of Science, says that “it’s too early to tell.” He adds that the Administration has already set its energy policy priorities as increasing oil drilling in Alaska’s Arctic National Wildlife Refuge, clean coal, and hydrogen. However, he says, “that doesn’t mean there isn’t room for new things.” With Congress close to passing an energy bill that focuses on tax breaks for oil exploration and hybrid cars, it doesn’t look as if a big push on solar energy will be one of those “new things” anytime soon. But Dehmer notes that progress on energy issues happens slowly. “I’m trying to lay the groundwork for a commitment on the scale of a major scientific user facility,” she says. At least compared with DOE’s earlier push for progress in hydrogen technology, many researchers expect that a push on E W S F O C U S solar energy research will be a far easier sell. “With hydrogen it was a lot more controversial,” Stupp says. “There are scientific issues that are really serious [in getting hydrogen technology to work]. With solar, it’s an idea that makes sense in a practical way and is a great source of discovery.” If that research and discovery doesn’t happen, Lewis says he’s worried about what the alternative will bring: “Is this something at which we can afford to fail?” –ROBERT F. SERVICE Re p r o d u c t i v e B i o l o g y A Powerful First KiSS-1 CREDIT: GETTY IMAGES Puberty researchers are finding that the protein kisspeptin and its receptor are central to this sexual maturation Both anticipated and dreaded, puberty is rarely fun. From swelling breasts and sprouting hair to cracking voices and unexpected urges, this transition is almost always awkward, especially if puberty comes earlier or later than normal. It is a rare teenager who has not wondered, “Why is this happening to me?” The body’s awakening into sexual maturity is no less puzzling for developmental biologists and endocrinologists. And they have an equally straightforward question: How does the body know when, exactly, to unleash the cascade of hormones that change face, voice, height, bone structure, and sexual organs into those of a fertile adult? The emerging answer, it seems, could have come from a teenage romance novel: Puberty starts with a kind of kiss. Are you ready? A protein called kisspeptin helps trigger the Recent studies have shown flood of hormones that marks puberty. that a protein called kisspeptin is Scientists hope the two proteins might a key trigger of the complex chain of physiological reactions that readies the body for help them solve long-standing puzzles sexual maturity. Without this signal, people, about the start of puberty, such as how the as well as mice and other mammals, stay in a body revives the hormone production that preteen limbo and never fully grow up. Dis- is prevalent in fetal and newborn developcovering the involvement of kisspeptin and ment but then mysteriously disappears durits receptor, a protein called GPR54, in ing childhood, and how puberty might be puberty “is a major breakthrough in repro- influenced by nutrition and other metabolic ductive physiology,” says Manuel Tena- factors. Preliminary evidence suggests, Sempere of the University of Cordoba in moreover, that the protein pair may even Spain. Indeed, the duo was one of the most- play a lifelong role in regulating sex discussed topics at a recent meeting on the hormones and reproduction. The topic is more than academic. For control and onset of puberty.* some children, puberty doesn’t happen at * 6th Puberty Conference, Evian, France, 26–28 May. the right time: Girls who start to develop www.sciencemag.org SCIENCE VOL 309 Published by AAAS breasts and pubic hair as young as 6 years old, and boys at 17 who still sing soprano often end up at the pediatrician’s off ice looking for answers. Although the physical consequences of being an early or late bloomer remain unclear, the social consequences can be signif icant. Boys who develop late may face brutal taunting because of their small stature and underdeveloped muscles. And early-developing girls “have higher rates of depression, substance abuse, and teenage pregnancies,” Pierre-André Michaud, a specialist in adolescent medicine at the University of Lausanne in Switzerland, said at the meeting. Consequently, physicians are eager to understand how puberty is controlled and whether they can, or should, safely delay or accelerate it in certain cases. KiSS-1-ng partner It was GPR54, not kisspeptin, that appeared first as a player in puberty. The initial clue was a 20-year-old man in Paris who had undeveloped testes, sparse pubic hair, and the bone maturity of a 15-yearold; such lack of sexual development is called idiopathic hypogonadotropic hypogonadism (IHH). Doctors soon discovered that the man was not the only one in his family to fail to complete puberty: Three of his four brothers were similarly affected, and one of his two sisters had experienced only a single menstrual period in her life—at age 16. All had abnormally low levels of sex hormones. It turned out that the parents of this family were first cousins and, as a team led by Nicolas de Roux of INSERM in Paris reported in 2003, both mother and father carried a mutation in one copy of their GPR54 gene. The affected children had all inherited two mutated copies of the gene. Other researchers had shown that GPR54 acts as a receptor for kisspeptin, so de Roux and his colleagues suggested that the molecular embrace between the two proteins might be a player in the first steps of puberty. 22 JULY 2005 551 E W S F O C U S A month after de Roux’s paper was hormonal signal. In cell-based assays, who become too thin, for example, published, that suggestion got a major kisspeptin “is one of the most powerful acti- become infertile and stop having periods. boost. Stephanie Seminara, Yousef vators of GnRH neurons ever seen,” says And people and mice with mutations in Bo-Abbas, and William Crowley of Har- Robert Steiner of the University of Wash- the genes coding for leptin or its receptor vard Medical School in Boston and their ington, Seattle. And in February, endocri- are infertile, apparently because of a colleagues reported that six members of a nologist Tony Plant of the University of failure to go through puberty. But further large Saudi Arabian family, all diagnosed Pittsburgh in Pennsylvania reported in the research failed to turn up direct conwith IHH, also had mutations in nections between leptin and their GPR54 genes. They also GnRH neurons. found that an unrelated patient There’s early evidence that with IHH carried mutations in kisspeptin may help mediate both his copies of the gene. In such a connection. In the June the same paper, researchers issue of Endocrinology, Tenafrom Paradigm Therapeutics in Sempere reports that rats kept Cambridge, U.K., reported that on a restrictive diet produce mice lacking the GPR54 gene less messenger RNA (mRNA) also failed to go through the from KiSS-1, consistent with rodent version of puberty. the idea that the gene responds Scientists at the time knew to leptin and other hormones very little about GPR54. They that signal the body’s nutriknew its gene was expressed in tional status. They also found the brain and the placenta, and that administering kisspeptin they knew the protein was a to underfed juvenile rats receptor for kisspeptin, which is could jump-start their delayed encoded by a gene called KiSS-1. puberty, perhaps bypassing the KiSS-1, on the other hand, was need for leptin to reach some fairly well known, but not among puberty threshold. endocrinologists. The gene was The KiSS-1 neurons, Steiner discovered by cancer researchers says, may integrate signals from at Pennsylvania State College of Leading lights. The neurons that express the KiSS-1 gene (white dots) a wide variety of body systems, Medicine in Hershey, Pennsylva- cluster in a region of the hypothalamus known to respond to sex hormones. such as how much food is availnia, who noticed that it played a able and even circadian clues role in the ability of tumor cells to move and Proceedings of the National Academy of such as time of day and season of year. The metastasize. (The romantic connection to Sciences that within 30 minutes of injecting connection may sound surprising, but puberty is accidental: The researchers juvenile male rhesus monkeys with researchers have long known that GnRH named the gene for the famous Hershey kisspeptin, the animals’ levels of LH and other sex hormones follow a daily chocolate drops.) increased 25-fold. rhythm and that the first hormone surges of Because of KiSS-1’s known role in cell puberty tend to occur at night. Steiner says motility, scientists initially thought that the Puberty’s puzzles he and his colleagues are looking for conkisspeptin-GPR54 pairing might influence Those results solidify the fundamental role nections between KiSS-1 neurons and the puberty by directing so-called GnRH of kisspeptin and GPR54 in puberty’s onset, brain’s circadian clock to see if they might neurons to the correct part of the brain. but it is not the whole story. “I’m not sure link the circadian and reproductive systems. GnRH neurons were identif ied more this is the discovery of the Holy Grail for But such work is still speculative. “The than 3 decades ago as the source of puberty,” Steiner says. “You need to have KiSS-1 neuron is far from characterized,” gonadotropin-releasing hormone (GnRH), this circuit operating for sure, but the con- de Roux cautions. a brain chemical that prompts the pituitary clusion that this is the ultimate switch for There is also evidence that the gland to produce follicle stimulating hor- puberty is probably premature.” kisspeptin-GPR54 signal helps regulate mone and luteinizing hor mone (LH). A missing link, for example, is what reproduction long past the first stirrings of Those signals in turn stimulate production turns the circuit on. Steiner and neuro- puberty. Steiner and his colleagues of sex hormones such as estrogen and endocrinologist Allan Herbison of the Uni- reported online in the 26 May issue of testosterone in the ovaries and testes. versity of Otago in Dunedin, New Zealand, Endocrinology that KiSS-1 neurons in the Kallmann syndrome, another condition are studying the neurons that produce the mouse brain carry estrogen receptors and in which patients fail to go through puberty, protein to find out what signals influence that levels of KiSS-1 mRNA in the brains of is caused by the improper migration of them. One of the most intriguing ideas is adult mice are modulated by injections of GnRH neurons during fetal development, that kisspeptin might be connected to the the hormone. And a group led by Keiichiro so researchers wondered whether a similar hormone leptin: Steiner said at the meeting Maeda of Nagoya University in Japan problem affected IHH patients with GPR54 that he has preliminary evidence that at reported online 23 June in Endocrinology mutations. But subsequent studies have least half of the neurons that express KiSS-1 that when they used antibodies to block the since shown that GnRH neurons are present also carry receptors for leptin. kisspeptin-GPR54 signal in adult female in the correct place and quantity in the A few years ago, many scientists rats, the LH surge that triggers ovulation GPR54-knockout mice. thought that leptin, which is produced by didn’t occur. “It is not just a switch that is Instead, the mutations may prevent the fat cells, was the key puberty trigger, pro- activated once,” Tena-Sempere says. It release of GnRH; GnRH neurons express viding a way for the body to delay sexual seems that, like the best kisses, KiSS-1 has GPR54 receptors, and their activation by maturation until it has enough stored long-lasting consequences. kisspeptin prompts the cells to release their energy to support reproduction. Women –GRETCHEN VOGEL 552 22 JULY 2005 VOL 309 SCIENCE Published by AAAS www.sciencemag.org CREDIT: R. STEINER/UNIVERSITY OF WASHINGTON N