Sex chromosome complement influences functional callosal myelination

Abstract

In addition to androgen differences between males and females, there are genetic differences that are caused by unequal dosage of sex chromosome genes. Using the cuprizone-induced demyelination model, we recently showed that surgical gonadectomy of adult mice resulted in decreased normal myelination and remyelination compared to gonadally intact animals, suggesting a supporting role for sex hormones in the maintenance of myelination. However, inherent sex differences in normal myelination and remyelination persisted even after gonadectomy, with males consistently remyelinating to a lesser extent relative to normal myelination as assayed by axon conduction and immunohistochemistry. This suggests a potential role for the sex chromosome complement in mediating the differential rates of remyelination observed in males and females. The present study focuses on the impact that sex chromosomes might have on these myelination differences. Making use of the four core-genotype \mice and cuprizone-diet induced demyelination/remyelination paradigm, our results demonstrate sex chromosome mediated asymmetry between XX and XY mice. The rate of functional remyelination following cuprizone diet-induced callosal demyelination in four core-genotype mice is attenuated in XY compared to XX animals of both gonadal sexes. Importantly, this difference arises only in the absence of circulating sex hormones following gonadectomy and confirms the role of sex hormones in the remyelination process reported earlier by our group. Because a genotype-mediated difference only arises following gonadectomy, the chromosomal contribution to myelination and remyelination is subtle yet significant. To explain this difference, we propose a possible asymmetry in expression of myelination-related genes in XX versus XY mice that needs to be investigated in future studies.

Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis

“…Similar to previous observations, corpus callosum (CC) of EAE mice showed many periventricular infiltrating lesions around blood vessels and scattered throughout white matter, accompanied by microglia/macrophage and reactive astrocyte accumulation and fewer enhanced green fluorescent protein on the proteolipid promoter (PLP_EGFP + ) OLs (13,14). EAE CC pathology resembles that observed in EAE DC.…”

Normal Development of the Corpus Callosum and Evolution of Corpus Callosum Sexual Dimorphism in Infancy

“…Furthermore, a study on brain development during puberty in adolescents demonstrated that sex steroids were related to sexual differences in the white matter microstructure . Moreover, sex chromosomes have been suggested to play a role in mediating the differential rates of remyelination observed in male and female mice . Although the exact mechanism of corpus callosum sexual dimorphism remains uncertain, we speculate that the maternal and placental gonadal hormones influence corpus callosum development.…”

“…42 Moreover, sex chromosomes have been suggested to play a role in mediating the differential rates of remyelination observed in male and female mice. 38,39 Although the exact mechanism of corpus callosum sexual dimorphism remains uncertain, we speculate that the maternal and placental gonadal hormones influence corpus callosum development. When neonates are disconnected from their mothers and the placenta, sexual dimorphism in the corpus callosum gradually becomes insignificant.…”

“…Sexual differences in the corpus callosum are attributed to genetic, hormonal, or environmental effects or a combination of these factors . The first study focused on the fetal corpus callosum, conducted by de Lacoste et al in 1986, suggested that gonadal hormones influence differentiation of the corpus callosum in the uterus.…”

“…combination of these factors. 38,39 The first study focused on the fetal corpus callosum, conducted by de Lacoste et al 36 in 1986, suggested that gonadal hormones influence differentiation of the corpus callosum in the uterus. Binding of gonadal hormones to specific receptors in the cell nucleus affects the transcription of a variety of genes.…”