The human testis-determining factor SRY localizes in midbrain dopamine neurons and regulates multiple components of catecholamine synthesis and metabolism

Authors

  • Daniel P. Czech,

    1. Molecular Genetics & Development Division, Prince Henry’s Institute of Medical Research, Monash Medical Centre, Melbourne, Australia
    2. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia
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  • Joohyung Lee,

    1. Molecular Genetics & Development Division, Prince Henry’s Institute of Medical Research, Monash Medical Centre, Melbourne, Australia
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  • Helena Sim,

    1. Molecular Genetics & Development Division, Prince Henry’s Institute of Medical Research, Monash Medical Centre, Melbourne, Australia
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  • Clare L. Parish,

    1. Florey Neurosciences Institutes, Melbourne, Australia
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  • Eric Vilain,

    1. David Geffen School of Medicine, University of California, Los Angeles, CA, U.S.A
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  • Vincent R. Harley

    1. Molecular Genetics & Development Division, Prince Henry’s Institute of Medical Research, Monash Medical Centre, Melbourne, Australia
    2. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia
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Address correspondence and reprint requests to Professor Vincent R. Harley, Prince Henry’s Institute of Medical Research, Level 4, Block E, Monash Medical Centre, 246 Clayton Road, Clayton, 3168, Australia. E-mail: vincent.harley@princehenrys.org

Abstract

J. Neurochem. (2012) 122, 260–271.

Abstract

The male gender is determined by the sex-determining region on the Y chromosome (SRY) transcription factor. The unexpected action of SRY in the control of voluntary movement in male rodents suggests a role in the regulation of dopamine transmission and dopamine-related disorders with gender bias, such as Parkinson’s disease. We investigated SRY expression in the human brain and function in vitro. SRY immunoreactivity was detected in the human male, but not female substantia nigra pars compacta, within a sub-population of tyrosine hydroxylase (TH) positive neurons. SRY protein also co-localized with TH positive neurons in the ventral tegmental area, and with GAD-positive neurons in the substantia nigra pars reticulata. Retinoic acid-induced differentiation of human precursor NT2 cells into dopaminergic cells increased expression of TH, NURR1, D2R and SRY. In the human neuroblastoma cell line, M17, SRY knockdown resulted in a reduction in TH, DDC, DBH and MAO-A expression; enzymes which control dopamine synthesis and metabolism. Conversely, SRY over-expression increased TH, DDC, DBH, D2R and MAO-A levels, accompanied by increased extracellular dopamine levels. A luciferase assay demonstrated that SRY activated a 4.6 kb 5′ upstream regulatory region of the human TH promoter/nigral enhancer. Combined, these results suggest that SRY plays a role as a positive regulator of catecholamine synthesis and metabolism in the human male midbrain. This ancillary genetic mechanism might contribute to gender bias in fight-flight behaviours in men or their increased susceptibility to dopamine disorders, such as Parkinson’s disease and schizophrenia.

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