Sexual differentiation of the brain is thought to be regulated by hormonal signals from the developing male gonad. However, more-recent experimental and clinical data throw some doubt on the general validity of the "classical" steroid hypothesis and suggest that additional intervening factors or mechanisms need to be considered. In particular, it is now envisaged that neurons are capable of acquiring sex-specific properties independently of their hormonal environment. Here we show that two Y-chromosomal genes involved in sex determination of the gonad, SRY and ZFY, are transcribed in hypothalamus, and frontal and temporal cortex of the adult male human brain. These genes are candidates for male-specific transcriptional regulators that could confer upon human brain cells the potential for hormone-independent realization and maintenance of genetic sex.

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Transient activation of the gene Sry in the gonadal ridge during a brief period of embryonic development is believed to function as a key signal for sex determination. However, a number of reports suggest that Sry expression is not as restricted in space and time as one would expect if its role was confined to directing male-specific differentiation in the early gonadal anlage. We have previously reported the occurrence of Sry/SRY transcripts in adult murine and human brain. The present communication is concerned with the study of the ontogenetic time course of Sry transcripts in mouse brain as detected by reverse transcription-polymerase chain reaction (RT-PCR). Particular emphasis was placed on the identification of two different forms of Sry mRNA, which can be linear or circular. To this aim, we used specific RT-PCR strategies to distinguish between both. Sry transcripts were found in male brain tissue of all ontogenetic stages investigated. Circular, presumably untranslatable, transcripts were found in embryonic brains of day 11 through 19. In contrast, postnatal Sry transcripts were linear, and thus translatable, and were found in diencephalon, midbrain, and cortex. The change from one transcript form to the other suggests that expression of the Sry gene in mouse brain is developmentally regulated, presumably by a switch in promoter selection. This supports the notion that Sry expression in brain is biologically significant.

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