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 th 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.