Glimpsing the birth of our earliest reproductive cells

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Formation of primordial germ cells gives insight into development and cancer

It has long been a mystery how the developing embryo designates those rare, precious cells destined to produce sperm and eggs — enabling us to have offspring – since these primordial germ cells’ existence is fleeting and hard to spot with the tools of biology. Now, using mouse embryonic stem cells, Harvard Stem Cell Institute(HSCI) researchers in the Stem Cell Program at Children’s Hospital Boston have managed to recapitulate the creation of primordial germ cells (PGCs) in the lab, capturing the stem cells’ gene activity as they differentiated to form PGCs. The findings, published on line by the journal Nature, also offer a unique window on cancer.

The researchers, led by George Q. Daley, a Professor in Harvard’s interschool Department of Stem Cell and Regenerative Biology, had a list of 30 genes they suspected of having a possible role in the development of PGCs. Using RNA interference (RNAi) techniques, they systematically disabled each one in turn to see if their absence affected PGC formation. They were able to catch embryonic stem cells in the act of differentiating into PGCs by testing them for genomic imprints, a set of genetic instructions affecting about 50 genes – knowing that these imprints disappear in PGCs. (The imprints are reestablished later when actual sperm and eggs are formed.)

To their surprise, Daley and colleagues discovered that a protein they had already been studying in the context of cancer and embryonic stem cells, known as Lin28, is essential for the formation of PGCs. When Lin28 was suppressed, PCGs did not develop.

Conversely, when the Lin28 gene was too active, the embryonic stem cells produced many more germ cells, suggesting that Lin28 regulates germ cell numbers. With this result in hand, the team suspected Lin28 might be linked to human germ cell tumors. Examining gene-expression data from malignant germ-cell tumors (mixed germ cell tumors, yolk-sac tumors, choriocarcinomas, embryonal carcinomas and seminomas), the researchers indeed found evidence of increased activity of Lin28 or the related protein Lin28B. Notably, this over-expression was confined to the malignant components of the tumors. In addition, tumors in mice treated with RNAi directed against Lin28 showed less invasiveness and proliferation.

“The ability to reproduce the earliest stages of gamete development in a Petri dish allowed us to discover Lin28’s role in germ cell development and malignancy,” says Daley, who is also a Howard Hughes Medical Institute Investigator. “In this case, studying embryonic stem cells has taught us an important lesson about cancer.”

Jason West, PhD, of the Biological and Biomedical Sciences program at Harvard Medical School, was first author on the paper. “Knowing Lin28 is deranged in germ cell cancers gives us a new target in the fight against this disease,” says West.

The study was funded by the National Institutes of Health (NIH), the NIH Director’s Pioneer Award, the Harvard Stem Cell Institute, the Burroughs Wellcome Fund and the Howard Hughes Medical Institute.