Genetic tug of war determines sexual differentiation

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.

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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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