"Long before it's in the papers"
December 22, 2009

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Females may harbor biological “inner male”

Dec. 22, 2009
World Science staff

In adult fe­male mice, switch­ing off one gene seems to start turn­ing the ovaries in­to tes­ti­cles and trig­gers the pro­duct­ion of male hor­mones at nor­mal male levels, sci­en­tists say.

The cu­ri­ous find­ings have led two re­search­ers to re­mark in a pub­lished pa­per that, bi­o­log­ic­ally speak­ing, fe­males may be en­gaged in a life­long “bat­tle to sup­press their in­ner ma­le.”

Both pa­pers ap­pear in the Dec. 11 is­sue of the re­search jour­nal Cell.

In a­dult fe­­male mice, switch­ing off one gene starts turn­ing the ovaries in­­to tes­ti­cles that pro­duce male hor­mones, sci­en­tists say. Above, John Couse, bi­ol­o­gist in the Na­tion­al In­sti­tute of En­vi­ron­men­tal Health Sci­ences and author of a pre­vious study on ro­dent "sex re­ver­sal," holds a fe­male mouse. (Im­age cour­te­sy U.S. Nat'l Inst. of En­vi­ron­men­tal Health Sci­ences)

The new results echo a pre­vious study that found that fe­male ovar­ian tissues in mice start to con­vert to male-like tis­sues in the ab­sence of sig­nals from es­tro­gen, a fe­male sex hor­mone. That stu­dy ap­peared in the Dec. 17, 1999 is­sue of the jour­nal Science.

In the newer re­search, N. Hen­ri­ette Uh­len­haut of the Eu­ro­pe­an Mo­lec­u­lar Bi­ol­o­gy Lab­o­r­a­to­ry in Hei­del­berg, Ger­ma­ny, and col­leagues were stu­dy­ing genes that dur­ing de­vel­op­ment are re­spon­si­ble for con­vert­ing glands called go­nads in­to ei­ther ovaries or tes­ti­cles, de­pend­ing on the sex.

Ovaries produce eggs, the fe­male sex cells, while tes­ti­cles produce sperm.

Uh­len­haut and col­leagues ge­net­ic­ally en­gi­neered mice in which the ac­ti­vity of a called Fox2L could be chem­ic­ally sup­pressed in the ovaries.

Fox2L, in turn, is a reg­u­la­tor gene that in­flu­ences the lev­el of ac­ti­vity of an ar­ray of oth­er genes. Among oth­er things, it keeps in check genes that tend to pro­mote tes­ti­cle de­vel­op­ment, ac­cord­ing to Uh­len­haut’s group.

Switch­ing off Fox2L had the im­me­di­ate ef­fect of in­creas­ing the lev­el of ac­ti­vity of some of these “tes­tis-specific” genes, the sci­en­tists re­ported. Crit­i­cal among these, they iden­ti­fied one called Sox9.

Con­com­i­tant with the boost in Sox9 ac­ti­vity was a “re­pro­gram­ming” of cer­tain ovar­i­an cell lin­eages in­to what ap­peared to be tes­tis cell lin­eages, Uh­len­haut and col­leagues found. Mean­while, the mod­i­fied ovaries be­gan pro­duc­ing nor­mal ma­le-like lev­els of the hor­mone tes­tos­ter­one.

“Our re­sults show that main­te­nance of the ovar­i­an phe­no­type [form] is an ac­tive pro­cess through­out life,” the sci­en­tists wrote.

It’s un­clear wheth­er the find­ings would trans­late to hu­mans, but be­cause mice share over 90 per­cent of their genes with hu­mans, it very of­ten hap­pens that mouse pro­cesses have par­al­lels in hu­mans.

It would seem “tes­tic­u­lar de­vel­op­ment is ac­tively re­pressed through­out the life of fe­ma­les,” added An­drew Sin­clair and Craig Smith of the Mur­doch Chil­dren’s Re­search In­sti­tute in Mel­bourne, Aus­tral­ia, in a pa­per pub­lished in the same is­sue of Cell. Sin­clair and Smith—the re­search­ers who in their ar­ti­cle metaphoric­ally sug­gested an “in­ner ma­le” may lurk with­in all fe­ma­les—also not­ed the find­ings go against “con­ven­tional wis­dom” that the ova­ry and tes­tis are “ter­mi­nally dif­fer­en­ti­ated,” or ir­re­versibly de­vel­oped to their ma­ture state. 

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In adult female mice, switching off one gene starts turning the ovaries into testicles that produce male hormones, scientists say. The curious findings have led two researchers to remark in a published paper that, biologically speaking, females may be engaged in a lifelong “battle to suppress their inner male.” Both papers appear in the Dec. 11 issue of the research journal Cell. In the research, N. Henriette Uhlenhaut of the European Molecular Biology Laboratory in Heidelberg, Germany, and colleagues were studying genes that during development are responsible for converting glands called gonads into either ovaries or testicles, depending on the sex. Uhlenhaut and colleagues genetically engineered mice in which the activity of a called Fox2L could be chemically suppressed in the ovaries. Fox2L, in turn, is a regulator gene that influences the level of activity of an array of other genes. Among other things, it keeps in check genes that tend to promote testicle development, according to Uhlenhaut’s group. Switching off Fox2L had the immediate effect of increasing the level of activity of some of these “testis-specific” genes, the scientists reported. Critical among these, they identified one called Sox9. Concomitant with the boost in Sox9 activity was a “reprogramming” of certain ovarian cell lineages into what appeared to be testis cell lineages, Uhlenhaut and colleagues found. Meanwhile, the modified ovaries began producing normal male-like levels of the hormone testosterone. “Our results show that maintenance of the ovarian phenotype [form] is an active process throughout life,” the scientists wrote. It’s unclear whether the findings would translate to humans, but because mice share over 90% of their genes with humans, it very often happens that mouse processes have parallels in humans. It would seem from Uhlenhaut’s findings that “testicular development is actively repressed throughout the life of females,” added Andrew Sinclair and Craig Smith of the Murdoch Children’s Research Institute in Melbourne, Australia, in a paper published in the same issue in the journal. Sinclair and Smith—the researchers who in their article metaphorically suggested an “inner male” may lurk within all females—also noted the findings go against “conventional wisdom” that the ovary and testis are “terminally differentiated,” or irreversibly developed to their mature state.