The long-term goal of our research program is to understand the mechanisms that control sexual differentiation of brain structures, behaviors, and diseases. The developmental process of brain sexual differentiation is critical for the establishment of dimorphism in neural function and behaviors between the sexes. Meanwhile, sex differences in the incidence, age of onset, and severity of neurobehavioral diseases are also well documented. Many studies have established an essential role for sex steroids and their nuclear receptors in these processes. However, the genetic and molecular mechanisms that underlie the actions of sex steroids on differential gene transcription and translation relevat to sex differences are still not clear. Recently, we have identified splicing factor, suppressor of white-apricot homolog (Drosophila) (Sfswap), also known as splicing factor arginine/serine-rich 8, as one of the many candidate genes differentially expressed in the neonatal mouse cortex between the sexes. Thus, we propose the novel hypothesis that sex steroids and their receptors regulate transcription of Sfswap gene in the developing cortex, which leads to sex difference in brain structures and behaviors. To test our hypothesis, the proposed project has three major aims: (1) to characterize expression of Sfswap gene in the mouse cortex during early development;(2) to examine if Sfswap expression in the cortex is regulated by perinatal exposure to elevated testosterone via androgen receptor;and (3) to investigate the physiological roles of Sfswap in the development of sexually dimorphic structures in the cortex and the behavior(s) mediated by this brain region. Our results will provide new important information on the functional link between alternative splicing and brain sexual differentiation. Successful completion of this project will also help the PI establish a new line of research in neuroendocrinology with the enhanced competitiveness and quality of research required to secure NIH non- SCORE funding in the future.
Sexual differentiation during early development has a significant subsequent impact on human health throughout life. Not only are gender differences well known in normal physiological function and behaviors but also in susceptibility to different diseases. Understanding the genetic and molecular bases of these gender differences will lead to better understanding and new treatments for sex-biased diseases.
|Armoskus, Chris; Moreira, Debbie; Bollinger, Kayla et al. (2014) Identification of sexually dimorphic genes in the neonatal mouse cortex and hippocampus. Brain Res 1562:23-38|
|Armoskus, Chris; Mota, Thomas; Moreira, Debbie et al. (2014) Effects of Prenatal Testosterone Exposure on Sexually Dimorphic Gene Expression in the Neonatal Mouse Cortex and Hippocampus. J Steroids Horm Sci 5:1000139|