Mouse Study Upends Bedrock Tenet of Reproductive Biology
Alla Katsnelson

For nearly a century, scientists have firmly believed that whereas men can
produce sperm throughout their lives, women are born with all the eggs they
will ever have. But new research suggests that this basic tenet of
reproductive biology is wrong, a discovery that could have enormous
repercussions for fertility treatment.
Egg cells, or oocytes, that are not fertilized are known to undergo a
natural process of cell death. While investigating the effects of
chemotherapy drugs on fertility in mice, Jonathan L. Tilly of Massachusetts
General Hospital and his colleagues began to count the normal rate at which
oocytes die. "We certainly didn't set out two years ago to overturn dogma,"
says Tilly, lead author of the report detailing the findings, published
today in Nature. But to their surprise, the scientists found that the number
of oocytes dying over a period of several days was far greater than would be
sustainable over the long term if the egg supply was not being replenished.
In fact, at that rate, mice would be fertile for just two weeks following
birth, as opposed to more than a year.

The team subsequently conducted a series of experiments to verify the
observation. Careful examination of the lining of adult mouse ovaries
revealed cells that closely resemble germline stem cells, those continuously
dividing cells that give birth to oocytes. The researchers determined that
these ovarian cells express a protein that is associated with meiosis, the
process by which sex cells divide. When they transplanted the putative
germline stem cells into a strain of transgenic mice whose cells all express
a green fluorescent marker, they found that the transplanted cells had
divided and produced oocyte follicles in the host tissue. Tilly and his
collaborators also analyzed the effects of a chemotherapy agent called
Busulfan on the mouse ovaries. The drug, which has been used to study sperm
proliferation, destroys the ability of male germline stem cells to divide
into new sperm, but does not harm existing sperm. Several weeks after
injecting the ovaries with Busulfan, the researchers found that the number
of oocytes had decreased dramatically. There was no sign of the cell death
that marks oocyte degeneration, however. The drug apparently targeted the
female stem cells, preventing their ability to produce oocytes.

Early in the 20th century, some scholars had suggested that eggs could in
fact be replenished in adult mammals. But a 1951 study definitively argued
that egg numbers are determined at birth, shutting the door to further work
for the next half century. "People were viewing ovaries very differently
than we do now," Tilly reflects. "The technology was just based on
histological analysis." Although biological markers for germline stem cells
have since been developed, conclusions about mammalian ovaries were never
reexamined because they were believed to be "as sound as telling people that
the sun sets in the west."

The team is now working to demonstrate the existence of germline stem cells
in human ovaries, and it is confident that the finding will carry over. The
next step is to figure out which genes instruct a germ stem cell to
differentiate into an egg. Ultimately, Tilly says, transplanting these cells
into the ovaries of menopausal women or women whose ovaries have been
prematurely damaged by cancer treatment could restore their fertility.

>From Scientific American
http://cl.extm.us/?fe8e11787561057a72-fe3016707360067c711779

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