Role for the membrane estrogen receptor alpha in the sexual differentiation of the brain

Abstract

Estrogens exert pleiotropic effects on multiple physiological and behavioral responses. Male and female sexual behavior in rodents constitutes some of the best‐characterized responses activated by estrogens in adulthood and largely depend on ERα. Evidence exists that nucleus‐ and membrane‐initiated estrogen signaling cooperate to orchestrate the activation of these behaviors both in short‐ and long‐term. However, questions remain regarding the mechanism(s) and receptor(s) involved in the early brain programming during development to organize the circuits underlying sexually differentiated responses. Taking advantage of a mouse model harboring a mutation of the ERα palmitoylation site, which prevents membrane ERα signaling (mERα; ERα‐C451A), this study investigated the role of mERα on the expression of male and female sexual behavior and neuronal populations that differ between sexes. The results revealed no genotype effect on the expression of female sexual behavior, while male sexual behavior was significantly reduced, but not abolished, in males homozygous for the mutation. Similarly, the number of kisspeptin‐ (Kp‐ir) and calbindin‐immunoreactive (Cb‐ir) neurons in the anteroventral periventricular nucleus (AVPv) and the sexually dimorphic nucleus of the preoptic area (SDN‐POA), respectively, were not different between genotypes in females. In contrast, homozygous males showed increased numbers of Kp‐ir and decreased numbers of Cb‐ir neurons compared to wild‐types, thus leading to an intermediate phenotype between females and wild‐type males. Importantly, females neonatally treated with estrogens exhibited the same neurochemical phenotype as their corresponding genotype among males. Together, these data provide evidence that mERα is involved in the perinatal programming of the male brain.

Estrogen receptor alpha, G‐protein coupled estrogen receptor 1, and aromatase: Developmental, sex, and region‐specific differences across the rat caudate–putamen, nucleus accumbens core and shell

“…Thus, the presence of nuclear ERα early in life provides a potential mechanism for organizational effects of hormones and sex differences on striatal neuron physiology that have been previously reported (Cao et al, 2016). Nuclear ERα expression does not exclusively organize sexual differentiation of the brain as a role for membrane or extranuclear ERα has also been described (Khbouz et al, 2019). It is unclear what the role of GPER1 in the nucleus may have in cell signaling.…”

“…for membrane or extranuclear ERα has also been described (Khbouz et al, 2019). It is unclear what the role of GPER1 in the nucleus may have in cell signaling.…”

17β-estradiol promotes acute refeeding in hungry mice via membrane-initiated ERα signaling

“…Our findings demonstrated an additional important role of membrane ERα in hypothalamic ERα neural populations, namely ERα ARH and ERα vlVMH neurons, in maintaining their acute responsiveness to either the ERα agonist or hypoglycemia. The role of membrane-bound ERα was also described to be important in the brain, especially for the organization of the circuits underlying sexually differentiated responses of the male brain [ 57 ]. In addition to the impaired fasting-induced refeeding, the ERα-C451A mutation also causes severe deficits in the glucose-sensing capability of ERα ARH and ERα vlVMH neurons.…”

Estetrol and Mammary Gland: Friends or Foes?

“…In transgenic mouse studies, ERα has been shown to mediate most of the estrogenic actions in organs including the brain, endothelium, mammary gland, vagina, and uterus. ERα has also been shown to control processes such as atheroprotection, vasodilatation, nitric oxide synthesis, endothelial healing, and bone demineralization, and is also involved in the prevention of type-2 diabetes [7,[42][43][44][45][46][47][48][49]. Two distinct signaling pathways are associated with ERα activation (reviewed in [50]): the genomic/nuclear pathway [51] and the non-genomic/extranuclear/membrane-initiated steroid signaling (MISS) pathway [50,52].…”