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ENDOCRINOLOGY
Protein Pegged to Onset of PubertyGPR54 May Also Be Tied to Disorders of Puberty, Endometriosis, Hormone-dependent CancersThe teen years are among the most mystifying in the human life span, and not just for parents. Adolescence begins when the hypothalamus, at the apex of the reproductive axis, sends out marked pulses of gonadotropin-releasing hormone (GNRH). After years of study, reproductive biologists still have not pinpointed the molecular players that allow the hypothalamus to transmit its puberty-inducing signal. Massachusetts General Hospital scientists, working with researchers at other institutions, have identified a gene, GPR54, that appears to play a critical role in getting out the message.
"Because we do a lot of clinical care and physiological investigation, our goal is to always think about further therapies and interventions that we can bring to our patients," said Stephanie Seminara, shown with (from left) William Crowely and James Acierno jr. (Photo by Graham Ramsay) Stephanie Seminara, William Crowley, and colleagues were first alerted to GPR54's role when they discovered a mutant version of the gene in people with idiopathic hypogonadotropic hypogonadism (IHH). Males with IHH fail to virilize--their voices do not deepen, their muscles and testes do not enlarge--unless treated. Females do not menstruate or develop normal breasts. Working with colleagues at Paradigm Therapeutics, a small biotechnology firm, the researchers found that mice lacking the GPR54 homologue exhibit symptoms of IHH. So compelling is the story that the New England Journal of Medicine broke a longstanding policy of publishing only clinical research. The article appears in its Oct. 23 issue. "This is the first time the Journal is publishing animal data, a historic event," said Seminara, HMS assistant professor of medicine. Conveying the Molecular MessageIt appears the role of the GPR54 protein is to get the GNRH message out of the hypothalamus, rather than to synthesize the hormone. Seminara and her colleagues found that mice lacking Gpr54 have normal levels of GNRH in their hypothalami. When injected with exogenous GNRH, the mice's pituitary glands, the next step along the reproductive axis, responded. "So the problem is in either the processing or the release of GNRH from the hypothalamus," said Seminara.
That such an important clue should lie with GPR54 would have struck many as unlikely a few years ago. Identified in 1999, the protein was little understood, other than that it was a G-protein-coupled receptor with an affinity for metastasin, a metastasis-suppressing ligand. "The literature about GPR54 was more in the cancer field," said Seminara. And there it might have stayed had Yousef Bo-Abbas, a former postdoc in Crowley's lab, not discovered a Saudi Arabian family with a large pedigree of IHH in his native Kuwait. Seminara, Crowley, and their colleagues used genetic linkage analysis to scour the family's chromosomes for defective genes. "The beauty of the technique is you do not come to the table with presuppositions about the gene," Seminara said. "You simply comb through every human chromosome until you find a signal from the data." They narrowed their search to the short arm of chromosome 19, then, using human genome maps, to a handful of genes. GPR54 caught their eye mostly because of the intriguing distribution of its protein--it appeared in the brain, pituitary, and placenta. "It had a bit of an endocrine feel to it," she said. Knockout EvidenceAs it turned out, GPR54 was defective not just in the Saudi family, but also in a patient that Seminara and her colleagues had seen in the MGH clinic. They had begun experiments to figure out how the defect was disrupting the patients' sexual maturation when Seminara received a telephone call from Steven O'Rahilly, a member of the advisory board of Paradigm Therapeutics. The company had just produced a knockout mouse that reproduced many of the symptoms of IHH. "He said to me, 'Stephanie, the mouse gene's human homologue resides in your region of chromosome 19,'" said Seminara. "He did not say the name of the mouse gene and I did not say GPR54, but we both knew. It was a wonderful moment."Not only did the mice reproduce symptoms of IHH, their pituitary glands responded positively to GNRH injections. It was only after they dissected the mouse hypothalami that the researchers found direct evidence of GPR54's possible role as exporter, rather than synthesizer, of GNRH. "We found the GNRH content of the hypothalamus was normal," said Seminara. "That really was the most powerful element of the data." Hormones are often clipped and cleaved before they mature. It is possible that the mice's lack of GPR54 may interfere with that process. "We do not know exactly what form of GNRH was sitting in the hypothalamus of the mice," she said. "It is also possible that GNRH is processed completely fine and is just not getting out." There is yet another intriguing option, one that Seminara and her colleagues will be exploring. Though the hypothalamus triggers puberty by sending out marked pulses of GNRH, it is not the first time that it releases the hormone. During embryonic development, waves of GNRH wash through the reproductive axis. Though they are greatly subdued soon after birth, the pulses never completely disappear. "GPR54 could be involved in the same system that is involved in the quieting of the axis after the first few months of life," she said. "It could be involved in the pubertal reawakening of the reproductive axis." --Misia Landau |
