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Genetic Tug Of War Determines Sexual Differentiation

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Duke Health News 919-660-1306

DURHAM, N.C. -- Whether or not a fertilized mammalian egg
ultimately develops into a male or female is determined by the
winner of a tug of war between two different genes encoding
signaling proteins and the divergent pathways they control,
according to a new study led by Duke University Medical Center
cell biologists.

In their experiments in mice, the researchers found that two
specific genes, Wnt4 and Fgf9, are in equal balance in the
early stages of development in the mammalian gonad before it
commits to either a male testis or a female ovary. If this
equilibrium is tipped in favor of Wnt4, the gonad develops into
an ovary, while an Fgf9 victory leads to the formation of a
testis.

What tips the balance in favor of male is a third gene, Sry,
located on the Y chromosome in the genome and known to be the
primary sex-determining gene in mammals. When this gene becomes
activated at a crucial moment in the early gonad's development,
it favors Fgf9 and leads to the development of a testis.

"We found that Sry accomplishes this feat by triggering
still another gene, the Sox9 gene. Sox9 activates the Fgf9 gene
which blocks Wnt4 and initiates a cascade of events leading to
the development of a testis," said Blanche Capel, Ph.D., senior
member of the international research team. "If XY mice lose
Fgf9, they develop ovaries, while XX mice that lose Wnt4
develop incomplete testes. This suggests that vertebrate sex
determination results from the interplay between these two
opposing signals."

The researchers published their findings in the May 22,
2006, issue of the journal Public Library of Science-Biology.
Their research was supported by the National Institutes of
Health.

In mammals, a fertilized egg with two X chromosomes will
become a female, while an egg with an X and Y chromosome will
become a male. However, during embryonic development, the gonad
has the ability to transform either into a testis or an ovary.
During the earliest stages of development, both XX and XY
gonads are characterized by similar patterns of Sox9, Fgf9 and
Wnt4 expression.

"If the Sry gene is not expressed at a critical point in
development, Sox9 and Fgf9 genes turn off, and the gonad
develops along the female pathway and becomes an ovary," Capel
said. "However, if Sry is expressed at this critical juncture,
Sox9 and Fgf9 become active and the process of becoming a
testis begins.

"The expression of these three genes leads to the formation
of specialized cells known as Sertoli cells, which then spur
the cascade of events leading to the formation of the future
seminiferous tubules of the adult testis," she continued. "Once
the testes are formed, they start producing testosterone, which
commits the whole animal to male development.

The researchers found that not only does Fgf9 stabilize the
expression of Sox9 and secure the male fate of the gonad, it
suppresses the activity of the ovary-promoting gene Wnt4, which
has the ability to block the testis pathway.

"In XX gonads, this Sox9-Fgf9 loop is not established, so
Wnt4 takes over, tilting the balance toward the female
pathway," Capel said. "Based on our findings, we believe that
the ultimate fate of the early gonads is controlled by mutually
antagonistic signals between Fgf9 and Wnt4."

Since the Sry gene occurs only in mammals, it is possible
that this antagonistic signaling between Fgf9 and Wnt4 may be
the mechanism that has remained common in the evolution of all
vertebrates, Capel said. She added that a different genetic or
environmental stimulus may tip the balance between these
signals in other species.

In nonmammalian vertebrates, other cues provide the primary
stimulus for embryonic gonad differentiation, Capel said. For
example, environmental temperature is the key to whether
reptiles develop along male or female pathways. Capel's team
will begin a new study this summer to better understand the
role of temperature on sex determination in a turtle that she
hopes can shed light on the general issue of sex determination
in vertebrates.

The research team also included Yuna Kim, Leo DiNapoli and
Jennifer Brennan from Duke. Other members included Akio
Kobayashi and Richard Behringer of the M. D. Anderson Cancer
Center in Houston; Ryohei Sekido and Robin Lovell-Badge of the
Medical Research Council's National Institute for Medical
Research in London; Marie-Christine Chaboissier of the Centre
de Biochimie in Nice, France; and Francis Poulat of the
Institut de Genetique Humaine in Montpellier, France.

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