Sexual dimorphism of oligodendrocytes is mediated by differential regulation of signaling pathways

Abstract

Sexual dimorphism of white matter has not been considered important, the assumption being that sex hormones are not essential for glial development. We recently showed exogenous hormones in vivo differentially regulate in male and female rodents the lifespan of oligodendrocytes (Olgs) and amount of myelin (Cerghet et al., 2006). To determine which hormones regulate male and female Olg development, we prepared enriched Olg cultures grown in serum free medium with estrogen (E2), progesterone (P2), and dihydrotestosterone (DHT) or their combinations. P2 significantly increased the number of Olgs in both sexes but more so in females; E2 had minor effects on Olg numbers; and DHT reduced Olgs numbers in both sexes but more so in females. Combinations of hormones affected Olg numbers differently than single hormones. The change in Olg numbers was not due to changes in proliferation but rather survival. P2 increased pAKT many-fold but MAPK levels were unchanged, indicating activation of the Akt pathway by P2 is sufficient to regulate Olg differentiation. DHT reduced pAkt in both sexes but differentially increased pMAPK in males and decreased it in females. Stressing Olgs reveals that both sexes are protected by P2 but females are slightly better protected than males. Females always showed greater differences than males regarding changes in Olg numbers and in signaling molecules. Given the greater fluctuation of neurosteroids in women than in men and the higher incidence of multiple sclerosis (MS) in women, these sexually dimorphic differences may contribute to differences in male and female MS lesions.

Regulation of astroglia by gonadal steroid hormones under physiological and pathological conditions

“…Sex also influences the inflammatory response of microglia; cells isolated from male rats exhibit an enhanced mRNA expression of IL-1β and CD14 than cells obtained from female rats, after exposure to LPS (Loram et al, 2012). Several sex differences in oligodendrocytes and myelin have also been described under physiological and pathological conditions (Byne et al, 2008;Cerghet et al, 2006;Johansson et al, 2012;Swamydas et al, 2009). Numerous sex differences in the development of astrocytes in both in vitro and in vivo models have been reported (Amateau and McCarthy, 2002;Beyer et al, 1990;Garcia-Segura et al, 1995;Mong and McCarthy, 2002) (Figure 1).…”

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

“…In addition, the distribution of ER-positive neurons (although not their overall numbers) forming the mesocortical system, which probably reflects their functional connectivity, was found to be sexually dimorphic (Kritzer and Creutz, 2008). As will be discussed in the relevant sections later, there is also evidence for sex differences in the mechanisms of intracellular signaling (Abrahá m and Herbison, 2005;Swamydas et al, 2009), in the expression of coregulatory proteins (Bousios et al, 2001), and in the response of the brain ER/aromatase SEX-SPECIFIC ESTROGEN ACTIONS IN THE BRAIN system to injury (Westberry et al, 2008). Together, such sex differences would theoretically have considerable influence on response to estrogens, although this remains to be investigated thoroughly.…”

Sexual dimorphism in the white matter of rodents

“…Different concentrations of progesterone (P2), estrogen (E2) and dihydrotestosterone (DHT), either alone or in various combinations, were added to enriched Olg cultures to determine their effects upon total cell numbers, proliferation, and cell death [46]. Female fluctuation of P2 concentration is well known and depends on the phase of estrous cycle [47] as well as pregnancy [48], supporting theoretical contribution of P2 to Olg sexual dimorphism.…”