27 Feb 2006

The male brain is guided by sex. No great surprise there, perhaps, except that in at least some parts of the brain this may have nothing to do with androgens, per se. A paper in the February 21 Current Biology reports that, in male rodents, the testes-determining factor Sry is essential for the proper function of dopaminergic neurons in the region of the brain that degenerates in people with Parkinson disease. Because Sry (for sex-determining region on Y chromosome) acts independently of testosterone, or any other sex steroid, the finding indicates that the Y chromosome can influence brain function irrespective of gonadal hormones.

The discovery speaks directly to the issue of sex differences. Whether sitting in a culture dish or being part of an organ bathed in sex hormones, every cell has a sex. This fundamental concept is sometimes overlooked, but an XY karyotype may not always behave the same as an XX in terms of gene expression. This is exactly what Eric Vilain and colleagues at the University of California, Los Angeles, have discovered about dopaminergic neurons in the substantia nigra (SN). They found that in the male SN, Sry is essential for full production of tyrosine hydroxylase, the enzyme that catalyzes the rate-limiting step of dopamine synthesis and which serves as a marker for dopaminergic neurons. Vilain and colleagues also found that silencing Sry in male mice leads to motor deficits similar to those experienced by people suffering from Parkinson disease.

Despite the fact that Sry appears to be the master switch determining testicular development, little is known about its mechanism of action. However, in 1993 one research group made the surprising discovery that Sry is expressed in adult tissues, including the brain (see Clepet et al., 1993). Later, Ingrid Reisert and colleagues at Ulm University, Germany, found that Sry is transcribed in the brain, leading the researchers to predict that Sry is involved in Y-chromosome, testosterone-independent sex differentiation in certain areas, including the hypothalamus and the midbrain (see Lahr et al., 1995).

Now, author Phoebe Dewing and colleagues bolster that view. They confirm that Sry is expressed in the brain and that levels are especially high in the SN, particularly the pars compacta where Parkinson pathology is thought to begin. They also discovered that Sry is expressed exclusively in dopaminergic neurons expressing tyrosine hydroxylase (TH). To determine if Sry has any effect on the activity of these neurons, Dewing and colleagues silenced the gene by infusing one side of rat brains with antisense oligonucleotides to Sry mRNA. This reduced the amount of TH in the neurons, but did not seem to otherwise affect them. Neuronal numbers stayed the same and there was no effect on Nur-related factor 1 (Nurr1), a transcription factor that is needed to kick-start expression of dopaminergic markers, such as TH, during development. This finding suggests that, at the very least, Sry and Nurr1 work in different pathways, or that the relationship between them is complex.

But TH is indispensable for production of dopamine, which is essential for the proper function of the SN and which is gradually lost in people with Parkinson disease. So it is not surprising that when the authors infused antisense Sry into one side of the SN, the animals developed difficulties moving their limbs on the contralateral side. This effect was reversible, because 7 days after infusion the animals made a complete recovery.

Exactly how Sry affects TH production is unclear, but TH transcription is a candidate target. Previous work showed that Sry may activate such genes as the AP1 transcription factor, which, like Sry itself, may bind to the TH promoter (see Milsted et al., 2004). Females, of course, have no Sry but still have plenty of TH neurons. This led Vilain and colleagues to speculate that, in males, Sry may be compensating for a factor that is normally present in females. That factor might be estrogen, because short-term administration of estradiol has been shown to increase TH in dopaminergic neurons of female rats, while ovariectomy has the opposite effect (see Serova et al., 2004).

How these findings relate to PD remains unclear at present. Vilain wrote by e-mail that he intends to check postmortem samples from PD and control brains for differences in SN Sry levels. He also plans to look for polymorphisms in the gene for Sry that might compromise the normal function of dopaminergic neurons in the SN.—Tom Fagan

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References

Paper Citations

1. Clépet C, Schafer AJ, Sinclair AH, Palmer MS, Lovell-Badge R, Goodfellow PN. The human SRY transcript. Hum Mol Genet. 1993 Dec;2(12):2007-12. PubMed.
2. Lahr G, Maxson SC, Mayer A, Just W, Pilgrim C, Reisert I. Transcription of the Y chromosomal gene, Sry, in adult mouse brain. Brain Res Mol Brain Res. 1995 Oct;33(1):179-82. PubMed.
3. Milsted A, Serova L, Sabban EL, Dunphy G, Turner ME, Ely DL. Regulation of tyrosine hydroxylase gene transcription by Sry. Neurosci Lett. 2004 Oct 21;369(3):203-7. PubMed.
4. Serova LI, Maharjan S, Huang A, Sun D, Kaley G, Sabban EL. Response of tyrosine hydroxylase and GTP cyclohydrolase I gene expression to estrogen in brain catecholaminergic regions varies with mode of administration. Brain Res. 2004 Jul 23;1015(1-2):1-8. PubMed.

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