Genetic determinants of mammalian brain sexual differentiation

• Main Author: Dewing, Phoebe
• Format: Dissertation
• Language: English
• Subjects: biology, animal physiology; biology, genetics; biology, neuroscience
• ISBN: 9780496090846; 0496090844

The central dogma of brain sexual differentiation asserts that gonadal steroid hormones from the developing embryo acts to promote sex differences in patterns of neural and behavioral development. However, growing evidence indicates that some sexual dimorphisms in the brain cannot be explained solely by the actions of hormones as they occur before the onset of sexually dimorphic secretions of the gonads. Thus a new theory emerges crediting a greater role for genetic determinants in influencing brain sexual differentiation. The overarching goal of the current study is to investigate direct genetic factors which may induce sex differences in neural sexual development. First, by using microarray technology, we detected more than 50 candidate genes which showed differential gene expression between the developing brains of male and female mice at embryonic stage 10.5 days post coitum, before the differentiation of the gonads. Second, we used the molecular mechanisms which control gonadal differentiation as a model to study direct genetic induction of brain sexual differentiation. We assessed the temporal and spatial mRNA expression of many sex determining genes in the brain and discovered that many of the genes with established roles in gonadal determination and differentiation were also expressed in the brain. One gene of particular interest was Sry, the master regulator of gonadal differentiation. By using in situ hybridization, we localized Sry mRNA expression to specific regions of the adult male brain, such as the cortex, substantia nigra, and medial mammillary bodies of the hypothalamus. Furthermore, by using antisense oligonucleotide injections, we found that down-regulation of Sry caused a decrease in tyrosine hydroxylase-immunoreactive neurons in the substantia nigra. Collectively, our results strongly suggest that hormones may not be the sole player in brain sexual differentiation. Rather, genetics and non-hormonal factors appear to have significant roles in sexual differentiation of neural circuits in the brain.