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

Daniel Peter Czech, Joohyung Lee, Helena Yin Yee Sim, Clare L Parish, Eric Vilain, Vincent Russel Harley

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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, D(2) R 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, D(2) R 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.
Original languageEnglish
Pages (from-to)260 - 271
Number of pages12
JournalJournal of Neurochemistry
Issue number2
Publication statusPublished - 2012

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